OsteoGeneX Inc.
This article was originally published in Start Up
Executive Summary
A discovery of the mechanism behind rare genetic condition sclerosteosis led to some new insights about bone growth. OsteoGeneX has now set out to discover small molecules that could inhibit the sclerostin pathway in a variety of potential applications including increasing bone growth in osteoporosis patients, spinal fusion and fracture repair.
Targeting the sclerostin pathway to promote bone growth
3800 Cambridge Street
Kansas City, KS 66160
Phone: (913) 945-6763
Web Site: www.osteogenex.com
Contact: Debra L. Ellies, PhD, President & CEO
Industry Segment: Biotechnology
Business: Developing therapeutics to assist in fracture healing
Founded: July 2006
Founders: Debra L. Ellies; William S. Rosenberg MD, CMO
Employees: 3
Financing to Date: $1.9 million
Investors: Angel Investors; NIH/NIAMS; Kansas Bioscience Authority; KTEC
Board of Directors: Debra L. Ellies; William S. Rosenberg
Scientific Advisory Board: Sigurd Berven, MD (University of California, San Francisco); Nancy Lane, MD (University of California, Davis Medical School); Harold Rosen, MD (Harvard Beth Israel Deaconess Medical Center)
Sometimes when a gene goes wrong, it can provide an unexpected boon. For sufferers of sclerosteosis, the mutated, non-functional form of the sclerostin protein is an unqualified disaster. Primarily found in Afrikaner populations in South Africa, the genetic condition causes the skull, jaw, and other bones to develop much higher bone density than normal.
But for patients with osteoporosis, bone fractures, and similar conditions, the discovery may herald a new form of therapy. While at the Stowers Institute for Medical Research, Debra Ellies investigated the mechanisms behind sclerosteosis. The sclerostin protein inhibits bone growth, and she discovered that it is regulated by activity of the LRP receptor.
Buoyed by her research success, in July 2006 Ellies decided to form OsteoGeneX Inc. and set out to discover small molecules that could inhibit sclerostin and lead to its decreased activity and an increase in bone growth. She also applied for and received a $134,000 Small Business Innovation Research (SBIR) grant from the National Institute of Arthritis and Musculoskeletal and Skin Diseases. To date, the company has raised a total of about $2 million in grants and investments.
The sclerostin pathway has a variety of potential applications. It could encourage increased bone growth in osteoporosis patients. It could also be used in surgical applications such as spinal fusion or fracture repair. The protein could even be manipulated in the other direction—a small molecule that promotes sclerostin activity could be used to control inappropriate bone growth such as osteosarcoma. Patients with sclerosteosis have high bone mass and no other apparent symptoms, which could be an indication that manipulating it might produce few side effects. "It’s a simple thing that we can mimic with therapy," says Ellies, who is now CEO of OsteoGeneX.
That can be contrasted with bone morphogenic protein-7 (BMP-7), which dominates the bone repair market. BMP-7 occupies an early position in the bone-building signaling cascade. As a result, it can influence a number of other processes. Because of that, women of child-bearing age are not allowed to take BMP therapies. "BMP is so far upstream, it has activities in many different pathways—so it’s a bit of a shotgun approach. There are all kinds of other possible effects," says William S. Rosenberg, OsteoGeneX’s chief medical officer.
OsteoGeneX’s technology is much more specific, he says. The sclerostin–LRP interaction inhibits bone growth and is quite specific to that activity. Small molecules that inhibit the receptor interaction should encourage natural bone growth. "It’s a laser focused solely on the osteoblast to create new bone, and as far as anyone can tell, that’s the only thing it’s doing. It’s much more biologically efficient than BMP." He also expects that it would be faster-acting than BMP-7 therapies, for the same reason.
OsteoGeneX has decided to out-license the osteoporosis application and use the revenue to focus development of a surgical product to assist with the healing of fractures, spinal fusion, and similar procedures. The company hasn’t signed any deals yet, but it is in discussions with interested parties, Ellies says. The osteoporosis market is about US $8 billion and growing, according to the National Osteoporosis Foundation.
BMP-7 is also used in surgical fracture repair, often applied to fractures to stimulate bone growth. However, its use is somewhat limited because it is difficult to store and handle. It comes packaged in sponges that tend to slip and may leach protein into surrounding tissues. "A small molecule that could be trained to behave better and attach to things would be an advantage," says Rosenberg.
Existing surgeries are often successful, but there is plenty of room for improvement, and that has prompted the development of a number of devices to further improve success rates. "Instead of 80% success rates, you want to achieve 99% success," says Ellies. Many such products are passive in nature—they allow bone growth to infiltrate the matrix surrounding the device, but they don’t actively encourage it. "In areas where there is a great deal of pull-out force or shear, such as a disc prosthesis where you want to maintain a mobile disc, you need to put an artificial plate of metal against the bone and have it stay there through 30 million (motion) cycles," says Rosenberg. A coating of sclerostin inhibitors could help promote bone growth and produce such stability.
The market is significant. According to a market report by Canaccord Adams, orthopedic markets were about US $24 billion as of 2006, and growing at about 10%. Many current therapies are based on bone BMP. Medtronic PLC is the leader with its INFUSE bone graft product. Stryker Corp.’s OP-1 implant is being developed for spinal fusion, fracture repair, and related indications. The BMP products represent about half of the market. The rest are largely composed of scaffolding material such as demineralized bone matrix or calcium salt that can be mixed with bone marrow or ground-up bone products, which include BMP proteins among their constituents. Those products have questionable efficacy, however, largely due to a lack of data.
In the osteoporosis field, Amgen Inc. is also exploiting the sclerostin pathway for osteoporosis with its antibody against sclerostin, currently in Phase I clinical trials. Other competing approaches include Nuvelo Inc., with antibodies that influence the Wnt pathway, which regulates cell growth and differentiation in a number of pathways, including bone growth.
These approaches focus on antibodies, partially because recent research has identified proteins responsible for inhibiting bone growth, making it a natural strategy to counter them with antibodies. Antibodies are also relatively easy to design. Nevertheless, biologicals have their drawbacks, including high price and storage issues. "I would say that’s one of our best positions, because we don’t have to manufacture a biological. We don’t have to store a biological either, and our shelf life should be much better," says Rosenberg.
The current regulatory environment might be the company’s biggest hurdle. Rosenberg anticipates that trials will begin in the next year or two, beginning with trials in Europe, but that plan is subject to change because the European Medicines Agency is considering making regulations considerably more stringent. "We will have to wait and see," Rosenberg says.
The FDA is also generating uncertainty. OsteoGeneX’s surgical product would follow FDA’s device pathway to approval, which includes a small safety trial followed by a pivotal trial for safety and efficacy. The number of patients required for such trials are much smaller than for new drug trials. But that could change.
"Probably the highest risk is the changing waters of the FDA," says Ellies. The agency recently established a new office of combination products, which would likely encompass OsteoGeneX’s surgical product. Depending on the timing of the change, the company might get through the regulatory process in time to be grandfathered in under existing regulations. If not, it will likely face increased costs and uncertainty. Ellies also predicts more stringent requirements. "The regulatory hurdles might become closer to pharma than devices," she says.
Although bone healing products are generally safe, there have been no randomized, blinded clinical trials to demonstrate efficacy. OsteoGeneX plans to conduct randomized, blinded trials, and Rosenberg hopes that they will help differentiate the company’s products from the competition. "I know that the clinical world is hungry for a more efficacious and cost-effective solution for bone formation. What has not been developed to date is something that is as specific to bone development and easily handled as what we’re developing right now. Hopefully that combination will be a clear advantage," says Rosenberg. –Jim Kling