By Debbie Strickland
Periodontitis sufferers will have to wait awhile — though how long isn't clear yet — for a pill that could inhibit the disease's advance. The FDA has requested clarification of the statistical methodology used in clinical trials for Periostat, an oral collagenase inhibitor developed by CollaGenex Pharmaceuticals Inc., of Newtown, Pa.
Periostat contains a sub-antibiotic dose of doxycycline and works by inhibiting collagenase, an enzyme that breaks down connective tissues. In periodontal disease, bacteria around teeth cause inflammation, triggering the release of collagenase and separation of gums from teeth. Severe forms of the disease eventually cause loss of teeth.
Current treatments kill or scrape away bacteria, whereas Periostat prevents gums from receding.
The new drug application for Periostat, accepted for filing in October 1996, was the first for CollaGenex, and the request for clarification marks the first FDA action letter sent on the product.
CollaGenex officials have discussed the matter with the agency via conference call and plan to meet with regulators, though a date has yet to be set.
"We believe that what we've provided is adequate and appropriate, but we need to go down there and convince them of that," said Brian Gallagher, president and CEO.
FDA officials "expressed a willingness to work with us," and, he said, the drug could still be approved this year.
"Really, the main question they've asked relates to the statistical methodology we've used. We used a very sophisticated, and what we think is a very appropriate, type of analysis, given that our drug is a systemic therapy for periodontal disease," said Gallagher.
Periostat is unlike other therapies for periodontal disease, which are administered locally and target the most severe sites.
"We treat the entire mouth," said Gallagher, "and so we believe the statistical methodology we employed is much more appropriate for this type of data set . . . We have a substantially larger database than would typically be done [for a site-specific therapy]."
CollaGenex's clinical trials generated up to six data points per tooth. So if a patient had 30 teeth, 180 data points theoretically could result. The analysis included all gum tissue: regions that were healthy, regions that were moderately diseased and those that were severely diseased.
Researchers and statisticians used General Estimating Equation techniques to crunch the numbers.
In Phase III trials involving 436 patients with periodontal disease (mild to severe), the drug showed statistical significance in preventing progression of the disorder. Patients took either a Periostat capsule or a placebo once or twice a day for one year, in addition to receiving traditional treatments to remove bacterial build-up.
According to the company, 67 million people have periodontal disease in the U.S., where each year, some 18 million periodontal procedures are performed at a cost of about $6 billion. Gallagher emphasized Periostat is an adjunctive therapy, and patients will "still need to deal with the bacterial component."
"It's analogous to hypertension, where there are ways of managing the disease and preventing the more severe effects," Gallagher said.
CollaGenex, which plans to market Periostat independently in the U.S., is already building a sales and marketing force to reach the dental community. The company in May launched its first product, Ponstel (mefenamic acid), a non-steroidal anti-inflammatory drug indicated for the relief of moderate pain. The company is selling the product in the dental market under a copromotion agreement with the Parke-Davis division of Morris Plains, N.J.-based Warner Lambert Co.
CollaGenex also is marketing a diagnostic product called Periocheck, approved by the FDA for use in monitoring periodontal disease. Periocheck measures the levels of tissue-destructive enzymes in gingival fluid.
At the earlier end of the pipeline, the company is developing Metastat, a treatment for metastatic cancer expected to reach the clinic this fall. The National Cancer Institute has agreed to sponsor development of the product, a chemically modified, non-antimicrobial tetracycline that has shown promise in preclinical studies in a variety of human tumor types as an inhibitor of tumor growth and metastasis. According to the company, the treatment is likely to be the first of a new class of matrix metalloproteinase inhibitors to reach the clinic.
CollaGenex has $27 million in cash, enough to last through 1998 — or longer, if necessary, according to the CEO. The company's shares (NASDAQ:CGPI) closed Tuesday at $12.25, up $0.875. *