Discovery Emerges as Dental Product for Bone Restoration

Many scientists hope their research will benefit people one day, but few of them actually leave their labs to take their findings into the clinic.

In November, a company founded and headed by a former faculty member at the Dental School announced the federal approval of its new product designed to help save the teeth of people undergoing surgery for chronic periodontitis. Other forms of the product are being developed for healing bone defects and fractures.

Image adapted by Rachel Eastwood from original courtesy of Bodell Communications, Inc.

A discovery at HSDM has led to a new therapy based on a mix of recombinant growth factor and synthetic bone substitute granules, which is applied under the gum to stimulate growth of new supporting bone, gingival tissue, and the external layer of the tooth root (cementum).

It appears to be the first discovery in a Harvard medical or dental lab to be commercialized by one of its inventors and developed into a successful drug product.

“It is quite a big deal for us,” said Prem Das, director of the HMS Technology Licensing Office. “This has the potential to benefit a large number of people.”

Below the Surface
Underneath receding gums, bacterial plaque can erode the bone and ligament supporting a tooth. The new product stimulates anatomically correct tissue regeneration by recruiting multiple cell types and other factors to the site. The cells form new supporting bone, ligament, gingival tissue, and the external layer of the tooth.

The product combines the company’s recombinant platelet-derived growth factor (PDGF) with commercially available synthetic bone substitute granules. A periodontist applies it once around a cleaned and surgically exposed tooth root. Then the gum is sutured back in place.

“The challenge has been to regenerate both bone and ligament,” said Samuel Lynch, the founder and CEO of BioMimetic Therapeutics. “If the ligament is not restored, the bone can fuse to the tooth root, creating a sensation like biting on a popcorn kernel.”

Sold under the name GEM 21S (short for growth-factor enhanced matrix), the treatment began as research in the HMS lab of Harry Antoniades, who helped discover PDGF, which forms the crucial component of the new product. Lynch joined Antoniades’s lab shortly after beginning a joint program for a Certificate of Specialty in Periodontology at HSDM and Doctorate of Medical Sciences at HMS in 1985. He continued studying the tissue repair potential of the growth factor when he became a faculty member two years later.

Over the next six years, studies by Lynch, Antoniades, and their colleagues generated nine U.S. patents and more than 70 foreign patents. During that time, they discovered that PDGF, previously known only to enhance skin healing, also improved bone and ligament regeneration, and that PDGF worked better in combination with certain other growth factors than by itself.

Meanwhile, Lynch also directed research in bone and tissue healing at the Institute of Molecular Biology, a small biotechnology company founded by Antoniades to explore potential applications for PDGF. Venture capitalists lost interest in the project, and in 1995, the company began to flounder. Yearning to bring the fruits of research to the clinic, Lynch left academia to oversee Osteohealth, a U.S. business unit of Sankyo focused on bone and tissue regeneration, which now markets GEM 21S through a deal with BioMimetic.

“A lot of fundamental discoveries in science happen in academic labs, but they do none of us any good if they stay in lab notebooks and aren’t developed into products that are widely available for our patients,” Lynch said. “People in academia cannot do everything that is required to develop a product and commercialize it and have it be widely available to help millions of patients. It is not the job of academics. It is the job of industry. It is vitally important that academia and industry not only cooperate but that the relationship is appropriately fostered.”

Entrepreneurship
The next year, Antoniades died of colon cancer, and PDGF lost a major scientific advocate. Soon, Lynch became aware that the growth factor technology was languishing, in part because a Seattle company controlled a crucial patent on the composition of the protein itself.

Lynch and his co-founders negotiated the necessary patent rights from this company and HMS and raised money from investors to start BioMimetic. He had to forfeit an initial pledge of $10 million from investors in New York and New Jersey when he moved to Nashville, Tenn., a move he promised to his wife and children upon leaving big pharma. By March 2001, however, he secured another $8.5 million in start-up money.

“By the time we founded BioMimetic in 2000, I had a clear vision scientifically of what I believed would work clinically, based upon combining PDGF with an appropriate matrix,” Lynch said. “For many years early on, we thought the protein was the most important key ingredient for stimulating healing. We did not fully appreciate the importance of combining the growth factor with a matrix. It serves a very important function by preventing collapse of scar tissue into the bone defect and providing scaffolding to foster and guide bone growth and deposition.”

In the complex drug development process, the main bump in the road for BioMimetic came when the company had to switch matrices. The bone-grafting material they used in early studies was popular with U.S. periodontal surgeons, but it is classified as donor tissue from humans, like blood, and so had not required or received FDA approval at the time. FDA officials could offer no quick or clear guidelines for designing trials that would lead to approval, Lynch said. To expedite the development process, the company changed to a previously approved synthetic bone substitute.

The pivotal clinical trial that led to FDA approval is one of the largest prospective randomized controlled studies on periodontal regeneration published in an English-language journal. In fact, the researchers completed a six-month follow-up on 98.9 percent of the 180 patients enrolled in the trial. The trial was conducted at 11 clinical centers, including the private practices of Myron Nevins and Marc Nevins, both HSDM faculty members and co-authors of the study, published in the December 2005 Journal of Periodontology.

“This is an encouraging large study with excellent follow-up,” said Ian Needleman, director of the International Centre for Evidence-Based Oral Health at University College London. Needleman estimates about half of the patients in his specialist periodontal practice would have a potential need for this product. But based on the published literature, he said, it is unclear how much benefit a patient could reliably expect compared to other surgical options.

BioMimetic has different formulations of recombinant PDGF in its preclinical and clinical development pipeline for orthopedic applications, Lynch said. The company has clinical trials in progress in other countries in fracture repair and foot and ankle osteotomies, and it hopes to begin U.S. trials in late spring. BioMimetic is also studying a nonsurgical way to increase bone density for treating or preventing vertebral compression fractures of the spine in people with advanced osteoporosis or to speed up healing of hip fractures in the elderly.

“It’s often shocking for researchers in academia to realize what it takes to develop and fully test a product, obtain FDA approval, and implement large-scale manufacturing sufficient to supply product to millions of patients,” Lynch said. “It can be a fantastic discovery in the lab, but it will usually take 10 to 15 years and tens of millions of dollars to turn it into a product that can treat patients.”

—Carol Cruzan Morton

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