New Studies Demonstrate That Lilly's Teriparatide Stimulates Bone Formation.

Business Editors/Health/Medical Writers

ROME--(BUSINESS WIRE)--May 9, 2003

Teriparatide Improves Bone Architecture and Reduces the Risk of

Moderate-to-Severe Vertebral Fracture by up to 95 Percent in

Postmenopausal Women with Osteoporosis

New studies presented at the 30th Annual European Calcified Tissue Society (ECTS) congress in Rome today showed favourable results for Lilly's teriparatide (Forsteo is the proposed trade name for Europe), in the treatment of established osteoporosis. The studies collectively provide further evidence that teriparatide stimulates bone formation, reduces the risk of vertebral fractures and, when compared with other agents such as alendronate, has a unique mechanism of action that significantly increases bone formation at the recommended dose of 20 micrograms.

An in-depth bone biopsy study, lead by Erik Eriksen M.D., global medical director for osteoporosis, Eli Lilly and Company, showed that teriparatide stimulates bone formation at two specific sites: the thin bars of bony tissue in spongy, trabecular bone and the thin layer of endosteal bone surrounding the bone marrow.(1) This further explains how teriparatide contributes to an overall improvement in patients with osteoporosis, which is significant because it is the deterioration of bone architecture that contributes to the weakening of bones and resulting fractures seen in patients with advanced osteoporosis.

The study, led by Dr. Eriksen when he was based at University of Aarhus, Denmark, investigated the effect of teriparatide on trabecular and endosteal bone. A total of 49 bone biopsies taken from patients after between 12 and 24 months of treatment with teriparatide were studied. It was found that daily treatment with 20 micrograms of teriparatide increased the number of osteons (the long cylindrical clusters that bone cells form) at both the trabecular and endosteal envelopes, leading to an increase in bone-forming activity.(1) The bone-forming activity caused by teriparatide leads to increased thickness in these areas of bone by up to 15 percent.(1)

"This biopsy study shows the ability of teriparatide to increase bone formation and build new trabecular bone, which is an important step in reducing the risk of fracture in patients with osteoporosis," commented Dr. Eriksen. "In addition, treatment with teriparatide reinforces the endosteal envelope, thus increasing the thickness and strength of cortical bone surrounding the bone marrow. Both of these contribute to an overall improvement in bone architecture."

"We do not often have the opportunity to conduct bone biopsy studies on this scale; however, the insights they can provide are invaluable," added Dr. Eriksen. "They are of particular importance in investigating the action of agents designed to treat osteoporosis at the skeletal level."

Second study shows fracture risk reduced with teriparatide(2)

A second teriparatide study, lead by John Christopher Gallagher M.D., chief of bone metabolism section, Creighton University, Omaha, Nebraska, revealed that, in women with severe baseline vertebral fractures, teriparatide reduced the risk of new vertebral fractures by 80 percent and of moderate-to-severe vertebral fractures by 95 percent compared with placebo.(2)

This new analysis builds upon research published by Neer et al. in the New England Journal of Medicine in May 2001,(3) where postmenopausal women with osteoporosis were given 20 micrograms of teriparatide once daily for a median of 19 months and results demonstrated the ability of teriparatide to stimulate new bone formation, increase BMD and reduce the risk of fracture.(2)

"This new analysis highlights the potential of teriparatide as a treatment to form new bone in women, even in those women with the most advanced form of osteoporosis," said Professor Gallagher. "It may be particularly suitable for those who experience the most pain and disability due to their osteoporosis."

Third study confirms greater bone turnover with teriparatide(4)

A head-to-head study comparing the different effects of teriparatide (20 micrograms per day) and alendronate (10 milligrams per day) on bone formation in postmenopausal women with osteoporosis (4) confirmed greater bone turnover with teriparatide. Bone biopsies after six months of treatment revealed that biochemical markers of bone turnover were significantly increased in the teriparatide group and significantly decreased in the alendronate group.(4) This confirms the difference in mechanism of action between teriparatide, which directly stimulates bone formation, and alendronate, which reduces bone remodelling.(4)

"For patients with established osteoporosis, a treatment such as teriparatide, which offers the unique ability to actively stimulate bone formation, has the potential to increase overall bone strength and lessen the likelihood of painful fractures," said Pierre Meunier M.D., professor of rheumatology and bone pathology, Laboratoire d'Histodynamique Osseuse, Faculte de Medecine Laennec, Lyon, France, who lead the study. "Teriparatide has the potential to offer new hope to patients and reduce the impact of the disease on their day-to-day lives."

Teriparatide received a positive opinion last year from the European Committee for Proprietary Medicinal Products (CPMP) and could be the first bone formation agent to receive marketing authorisation in Europe.

The drug will be known as Forteo in the rest of the world and was launched in the United States in December 2002.

Side effect profile of teriparatide

In studies with teriparatide, the most frequent treatment-related adverse events were generally mild to moderate and dose related. At the 20 microgram dose, dizziness or leg cramps were reported in nine percent and three percent of women, respectively; compared with six percent and one percent on placebo.

Development of this investigational drug was suspended in December 1998 to evaluate a carcinogenicity study in rodents. In the study, rats given teriparatide starting early in their lifetimes and treated with the drug for nearly their entire lifetimes developed bone tumours, including osteosarcomas. No bone tumours occurred in human patients in the clinical trials. A comprehensive assessment by external oncology experts and company researchers indicated that the finding in rats was unlikely to predict an increased risk of osteosarcoma for humans receiving teriparatide for the intended clinical use. This conclusion was based, in part, on several important differences between rat and human bone biology and responses to teriparatide.

Lilly, a leading innovation-driven corporation, is developing a growing portfolio of best-in-class pharmaceutical products by applying the latest research from its own worldwide laboratories and from collaborations with eminent scientific organisations. Headquartered in Indianapolis, Ind., Lilly provides answers - through medicines and information - for some of the world's most urgent medical needs.

(1) Eriksen EF, et al. Teriparatide Increases the Width of

Modeling and Remodeling Osteons at the Trabecular and

Endosteal Envelope. Abstract presented at the European

Calcified Tissue Society Meeting, Rome, May 8-12th 2003.

(2) Gallagher JC, et al. Teriparatide Reduces the Risk of

Vertebral Fractures Regardless of Baseline Vertebral Fracture

Number and Severity. Abstract presented at the European

Calcified Tissue Society Meeting, Rome, May 8-12th 2003.

(3) Neer RM, et al. Effect of parathyroid hormone (1-34) on

fractures and bone mineral density in postmenopausal women

with osteoporosis. NEJM 2001; 344(19): 1434-41.

(4) Meunier PJ, et al. Diverging Effects of Teriparatide and

Alendronate on Bone Formation in Postmenopausal Women with

Osteoporosis. A Histomorphometric study. Abstract presented at

the European Calcified Tissue Society Meeting, Rome, May

8-12th 2003.