By Anissa Anderson Orr

KANSAS CITY, MO—Osteoporosis thins out and weakens bones, making them more prone to breaking. About 10 million people in the United States have osteoporosis, and postmenopausal women with the disease are particularly susceptible to fractures, which can be life-altering events leading to the loss of mobility.

While standard treatments help stave off bone loss, they don’t replace lost bone. The new drug romosozumab, approved by the US Food and Drug Administration in January 2019 and developed by Amgen in collaboration with the Belgian biopharmaceutical company UCB, is the first drug that promotes bone growth. The injectable monoclonal antibody, sold under the brand name Evenity, works by blocking a protein, sclerostin, that inhibits the buildup of bone.

This new treatment for osteoporosis was made possible in part by an unexpected discovery made by Stowers researchers nearly two decades ago. The researchers uncovered a mechanism that controls bone growth. Krumlauf and former lab member Debra Ellies, PhD, published the work, which the Institute also patented. The intellectual property was licensed to Amgen in 2005.

Foundational research paved way for new drug

The discovery that guided the development of romosozumab arose out of basic research into Hox genes, which play a key role in the formation of body structures, including bones.

In the early 2000s, Krumlauf’s team identified a specific signaling pathway that regulates Hox genes and found that the same pathway also controls the buildup of bone. The researchers discovered a protein related to sclerostin, called Wise, and showed that both proteins inhibit the Wnt signaling pathway by binding to co-receptors on the surface of cells. This finding was unexpected because work on related molecules suggested that they were likely to block a different pathway.

Over the next decade, the lab conducted experiments to deepen their understanding of how Wise and sclerostin controlled bone loss. They knew they were on the right track when a mouse model they developed that lacked the gene for Wise had much stronger bones than mice with functional copies of the gene.

“That was the ‘Aha!’ moment for us. The Wnt signaling pathway looked like it was playing a really critical role in laying down new bone. We thought this could be a really important discovery,” Krumlauf says.

In addition to Krumlauf’s research, scientists from other institutions had spent decades studying Afrikaner patients who had bones that didn’t break. This condition caused health problems ranging from overgrown skulls, deafness, and severe headaches to fingers that fused together.

In 2001, the scientists reported that these effects resulted from a single gene mutation that blocked expression of sclerostin.

According to Krumlauf, Wise is important for laying down new bone during early development while sclerostin is important for laying down bone in adults. Findings about both of these related proteins have been instrumental in understanding how the body builds bone.

Stowers enables findings that stimulate medical advances

Krumlauf says Stowers’ support was critical for translating his findings from a laboratory discovery to a potentially life-changing therapy for osteoporosis. With the freedom to pursue foundational research and follow the new directions it might take instead of focusing on a narrow line of study, his lab made an unexpected discovery that has great potential for improving human health.

The Institute also leveraged its relationship with BioMed Valley Discoveries, a discovery development organization co-founded by Jim and Virginia Stowers, to shepherd the discovery through the patenting and licensing process, which can be time-consuming and expensive for researchers to handle on their own.

“What I’m proud of is that the Institute helped us protect our discovery and understand its value. The BioMed Valley Discoveries team found a way to guide it to the right people, with interests in developing and using it, and now we’re on the threshold of it being able to make a difference in human health,” Krumlauf says.

Amgen spent the next decade conducting additional preclinical studies and human clinical trials to take Krumlauf’s discovery and others’ findings about bone growth to the next level. Romosozumab is an antibody that mimics the mutation found in the Afrikaner patients by blocking sclerostin from binding to its receptor.

The FDA based its approval of Evenity on the results of two Phase 3 clinical trials, which showed a significant reduction of fractures. One year of treatment with the drug lowered the risk of new spinal fracture by 73% compared to placebo. The drug also increased bone density in the spines of study participants by around 15%, which is significant and similar to spurts of growth in adolescence.

The approval of Evenity represents the first new drug aided by research from Stowers and reinforces the Institute’s core belief that unexpected connections resulting from basic research have practical benefits in supporting the development of new medicines and therapies. Krumlauf and Ellies did not seek to study osteoporosis when they were trying to understand the mechanism by which sclerostin acted. Their fundamental studies led to unexpected insights into how a potential treatment for osteoporosis could work.

In addition to Krumlauf and Ellies, the research was assisted by former Stowers researcher Youngwook Ahn, PhD. Contributors from other institutions included Nobue Itasaki, PhD, at MRC National Institute for Medical Research UK, and Scott Saunders, MD, PhD, at Washington University Medical School. The Krumlauf Lab continues to investigate how the pathway that controls bone buildup may potentially affect other organs and tissues.