Device companies and contract manufacturers have dedicated extensive efforts to develop coatings, additively manufactured constructs and orthobiologics to promote osseointegration. When the National Institute of Health (NIH) awarded a grant to a computational drug discovery company applying artificial intelligence (AI) and researchers at Mayo Clinic to study joint replacement coatings, we took notice of this non-traditional pair in orthopedics.
The collaboration between Numerate and Andre J. van Wijnen, Ph.D., Professor of Biochemistry and Molecular Biology and Orthopedic Surgery at Mayo Clinic, demonstrates the continued interest of non-device companies employing advance technologies to answer essential orthopedic questions. Their project, titled “EZH2 inhibitors as endoprosthetic device coatings that induce osteogenesis and promote implant osseointegration,” seeks to identify drug options for use in orthopedic implant surface coatings, including those for knees and hips.
“There is a clear unmet need when it comes to orthopedic applications promoting better osseointegration,” says Uwe Klein, Ph.D., Vice President of Biology at Numerate and Principal Investigator on the project. “Over the years, a lot of research has focused on biologics; there are a lot of companies that have developed biologics and new device coatings to help with osseointegration. Still, aseptic loosening of implants is a big issue, particularly in patients that have impaired bone regeneration.”
New insights into triggers for bone formation emerging from Dr. van Wijnen’s research attracted Numerate and us to the research.
What’s the Basis for the Research?
For years, Dr. van Wijnen’s lab has studied how bone formation is biologically regulated. The research led him to identify epigenetic factors that are key gatekeepers for the differentiation of stem cells into bone forming cells, according to Dr. Klein.
“What that means is that if you inhibit the [EZH2] enzyme, be it through biological mechanisms or small molecule drugs that we discover using our computational platform, you will release the epigenetic repression of genes and stimulate stem cells to differentiate along the osteogenic lineage to form bone,” Dr. Klein says.
Numerate and Dr. van Wijnen, Co-Investigator on the project, seek to discover small molecule drug compounds that could be used in drug/device combinations in orthopedic procedures, like knee and hip replacement, spinal fusion or even dental implants. The combination of drug and device is expected to support integration of existing bone with the implant—which in turn could reduce complications from implant loosening and potentially increase the lifetime of an implant, which is especially valuable in patients with disorders that impact new bone formation and repair, like diabetes, osteoporosis and osteoarthritis.
“You can coat the surface of the implant with the compound which, through inhibition of the enzyme, would trigger osteogenic lineage commitment of stem cells and stimulate formation of new bone at exactly the device/bone interface,” Dr. Klein says.
What’s Behind the Research?
Numerate has developed a computational platform that applies AI at cloud scale to transform small molecule drug discovery, which is applicable across a range of therapeutic areas, including orthopedics, cardiovascular, oncology, etc.
When asked to describe the approach, John Griffin, Ph.D., Numerate’s Chief Scientific Officer explained it like this. “More than a decade ago, we saw that productivity of traditional methods of drug research and development were not meeting the needs and opportunities presented by modern biology. Traditional processes related to industrialized serendipity of manufacturing compounds and testing them in the laboratory in repeated iterative cycles doesn’t make use of the knowledge that is inherent in all of the work that has gone into industry around any individual program. That was occurring at a time when there was a confluence of unlimited computational power being made available to the general public in the form of cloud computing, and ever more data being generated and publicly available to which one can then apply computational methods. By applying new-generation machine learning (artificial intelligence) algorithms, one can extract wisdom from all of that information and apply it in a forward sense to identify new drug candidates.”
Specific to this orthopedic project, Numerate’s platform is scouring peer-reviewed literature, patents, presentations and public and commercial databases to extract data and build computational models that are used to discover novel compounds that potently inhibit the EZH2 enzyme and that possess the right properties to allow for inclusion in a device coating.
The highest ranked compounds identified through use of the platform are selected for synthesis and labbased testing to verify biochemical activity. Researchers at the Mayo Clinic then confirm their ability to induce differentiation of stem cells into bone forming cells in a tissue culture dish.
The Phase 1 SBIR grant from the National Institute of Arthritis and Musculoskeletal and Skin Diseases division of the NIH is funding this step of the project, which is expected to be complete in mid-2019.
Next Steps for the Research
In the next phase of the project, the group plans to demonstrate that the identified compounds can introduce differentiation of human stem cells into bone forming cells on a modular surface that would mimic what occurs with an orthopedic implant, and also demonstrate compound effects in a mouse model in vivo. Dr. Klein says there are a number of options for this research, including depositing the compound on a hydroxyapatite coated titanium implant, or incorporating the compound into bone cement.
Following discovery of a drug lead during the research phase of this program and completion of the required safety studies, the team plans to file an Investigational New Drug Application and clinical studies in an indication that allows for rapid proof of the envisioned concept.
However, the research is in early stages at the moment, and further funding via an extension of the NIH grant or via public or private investments is needed for the next phase. Dr. Griffin says that good progress has been made, and multiple third-party companies have already shown unsolicited interest in the project.
“We think that our approach is novel,” says Dr. Klein. “There are a lot of benefits to biologics, but they also have drawbacks. There are many things you can’t do with biologics that you can do with small molecule drugs in combination with a device, which we are planning to develop here.”