New Phase III Results Show Lilly's Investigational PTH Improves Bone Strength and Reduces Fracture Risk in Women With History of Fracture.

European Business & Health/Medical Editors

MADRID, Spain--(BW HealthWire)--June 6, 2001

Separate Studies Prove Sustained Effect of Evista(R), Show Boosts in

BMD Account for Only Small Proportion of Fracture Efficacy

Leading researchers today presented new clinical trial data for Eli Lilly and Company's (NYSE:LLY) osteoporosis compounds -- its investigational parathyroid hormone (PTH) and its marketed selective estrogen receptor modulator (SERM) Evista (raloxifene hydrochloride) -- at the first joint meeting of the International Bone and Mineral Society and European Calcified Tissue Society.

Results from a pivotal Phase III study of rhPTH (1-34), Lilly's recombinant form of the human PTH protein, show that it significantly reduced the risk of spinal and nonspinal fracture and improved cortical bone strength among postmenopausal women who have a history of osteoporosis-related fractures. Lilly will be submitting rhPTH (1-34) (teriparatide injection (rDNA origin)) to the European Medicines Evaluation Agency for review this year. If approved, it would be the first in a new class of drugs called "bone formation agents" available to treat postmenopausal osteoporosis.

A separate osteoporosis treatment study with Evista demonstrated a sustained fracture risk reduction through four years of treatment. Evista, the first SERM available to prevent and treat postmenopausal osteoporosis, is marketed in more than 70 countries worldwide.

"Over the last decade, Lilly has committed tremendous resources to the research and development of SERMs and a bone formation agent in an effort to make available new, first-in-class therapies that will help a broad range of women prevent the consequences of osteoporosis," said John Lechleiter, Ph.D., Lilly executive vice president, pharmaceutical product and corporate development. "Our emerging research with both Evista and PTH indicates that medications can help women with osteoporosis despite the progression of the disease," he said.

New rhPTH (1-34) Study Findings

Two researchers (Erik Eriksen, M.D., D.M.Sc. of Aarhus Amtssygehus in Denmark, and Stefan Goemaere, M.D., of Ghent University Hospital in Belgium) presented fracture findings from Lilly's pivotal Phase III study of rhPTH (1-34) that assessed the effects of 20 mcg and 40 mcg dosage versus placebo. Primarily undertaken to determine the effects of Lilly's PTH on fracture risk reduction and BMD in women with osteoporosis and prior fracture, the study also evaluated the effects of rhPTH (1-34) on several properties of cortical bone. Emerging research suggests that cortical bone thickness and strength may play a role in fracture risk reduction independent of BMD.

-- Reduced Fracture Risk. Compared with placebo, rhPTH (1-34) significantly
reduced the risk of new spinal fracture by 65 percent (20 mcg) and 69 percent
(40 mcg) in women with one or more spinal fractures(1)(9). The risk of
nonspinal fractures resulting from osteoporosis (fragility fractures) was
lowered overall by 53 percent (20 mcg) and 54 percent (40 mcg) compared with
placebo(2)(9).

-- Reduced Fracture Severity. Lilly's pivotal Phase III study also evaluated
the grade or severity of fractures that occurred among study participants.
rhPTH (1-34) 20 mcg reduced the risk of moderate and severe fractures by 90
percent and 40 mcg reduced this fracture risk by 78 percent, compared with
placebo(1)(9).

-- Reduced Impact of Fracture. Study investigators also evaluated the incidence
of new or worsening back pain and height loss, which are often consequences of
the disease. Results showed PTH treatment significantly decreased height loss
(p less than 0.001) and back pain (p less than 0.015) compared with the placebo
treated group(1)(9).

"It is important for osteoporosis studies to evaluate effects

on height loss and back pain, as improvement in these areas

may make the daily life of a woman with an advanced form of

osteoporosis more bearable," Eriksen said.

-- Improved Cortical Bone Thickness and Bone Strength. As part of

the larger Phase III trial, two study sites also assessed the

effects of rhPTH (1-34) on cortical bone thickness and

measures related to cortical bone strength. Cortical bone is

the dense, outer shell of bone that encases the internal,

spongy-like trabecular bone. Osteoporosis therapies typically

produce greater increases in BMD at the predominantly

trabecular regions of bone (such as lumbar spine) than

cortical regions (such as the midshaft radius).

Lars Hyldstrup, M.D., of the University of Copenhagen and

Hvidovre Hospital in Denmark, reported that rhPTH (1-34)

treatment resulted in thicker cortical bone(3). Jose R.

Zanchetta, M.D., of the Instituto de Investigaciones

Metabolicas and USAL University School of Medicine in

Argentina, reported that among rhPTH (1-34) treated women,

cortical bone was added to the outer surface of bone, where it

contributes more to strength than adding bone to the inner

surface(4).

"These findings suggest that PTH treatment may affect factors

related to skeletal quality and strength," said Zanchetta. "It

is possible that these effects on cortical bone -- which

cannot be detected by BMD testing -- are contributing to the

significant reduction in fracture risk seen with PTH treated

women in the broader Phase III study."

Evista Shows Sustained Effects in Preventing Spinal Fractures

Jean-Yves Reginster, M.D., Ph.D., of CHU Centre-Ville in Belgium, presented four-year data from the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, a placebo controlled study that involved more than 7,700 women with osteoporosis at 180 sites worldwide. Three-year fracture data from this study served as the basis for the drug's current osteoporosis treatment indication.

Four-year analyses of the MORE data showed the following for women taking Evista (raloxifene 60 mg) compared with those taking a placebo:

-- a significant reduction (68 percent) in the risk of new

clinical (painful) spinal fractures one year after initiating

Evista treatment(5)(8)

-- a significant reduction (49 percent) in the risk of new spinal

fractures at four years of Evista treatment among women with

no prevalent (prior) spinal fractures(5)(6)

-- a significant reduction (34 percent) in the risk of new spinal

fractures at four years of Evista treatment among women who

had prevalent (prior) spinal fractures(5)(6)

Researchers also conducted an analysis that confirmed the fracture risk reduction observed at year four of Evista therapy is comparable to that observed in years one through three of therapy(5)(6).

"The four-year analysis of MORE data confirms Evista's rapid onset of action and patient benefit," noted Reginster. "Further, the concept of `sustained efficacy' is important because it demonstrates that the protective effects seen in the early years of Evista therapy do not wane over time. This sustained effect was observed among women with and without prior spinal fractures."

Similar data sets have yet to be presented for other antiresorptive agents.

Does BMD Measurement Truly Predict Fracture Risk?

The MORE study also evaluated the role of BMD as a predictor of fracture risk. BMD testing is currently the most widely used tool to diagnose osteoporosis and evaluate the success of subsequent treatment.

Nelson Watts, M.D., director of the Osteoporosis and Metabolic Bone Diseases Center at the University of Cincinnati, examined the MORE data and applied new statistical methods to determine the relationship between change in bone density and reduction in fracture risk with treatment. He concludes that BMD accounts for only a small portion -- about 10 percent -- of the fracture risk reduction seen with Evista(8). Analyses undertaken with other antiresorptive agents have shown similar results.

"In people who are not receiving treatment for osteoporosis, there is a strong relationship between bone density and the risk of fracture. However, this and other research strongly suggests increases in BMD in response to treatment do not tell us to what extent an osteoporosis therapy is working to reduce the risk of fracture," Watts said. "Research is emerging in this area, and we hope to identify other methods that can accurately predict the effect of treatment to reduce fracture risk."

Adverse Effects

In studies with rhPTH (1-34), the most frequent treatment-related adverse events were generally mild to moderate and dose related. At the 20 mcg dose, dizziness or leg cramps were reported in 9 percent and 3 percent of women, respectively, compared with 6 percent and 1 percent on placebo. At the 40 mcg dose, nausea or headache occurred in 18 percent and 13 percent, respectively, compared with 8 percent and 8 percent on placebo.

Evista use was associated with some side effects, the majority of which were reported as mild. The most common side effects were an increase in hot flushes and leg cramps. Deep vein thrombosis, or blood clots in the veins, is a rare but serious side effect. DVT is observed at a rate similar to that seen with HRT. Women who are or can become pregnant, are breast-feeding or women with existing endometrial or breast cancer should not take Evista. It should also not be taken by women with liver disease or those with unexplained vaginal bleeding.

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 organizations. Headquartered in Indianapolis, Ind., Lilly provides answers -- through medicines and information -- for some of the world's most urgent medical needs.

Evista(R) (raloxifene hydrochloride, Lilly)

(1) G. Goemaere et al. Treatment with recombinant human parathyroid ((1-34)) decreases the severity and sequalae of vertebral fractures. Abstract OR29 Presented at the International Bone and Mineral Society Meeting. June 2001. (2) E.F. Eriksen et al. Effect of trauma assessment on nonvertebral fracture risk reduction in the recombinant human parathyroid ((1-34)) fracture prevention study. Abstract SC12T Presented at the International Bone Mineral Society Meeting. June 2001. (3) L. Hyldstrup et al. Assessment of Effects of LY333334 (recombinant human Parathyroid Hormone ((1-34))) on Cortical Bone using Digital X-ray Radiogrammetry. Abstract SC335 Presented at the International Bone Mineral Society Meeting. June 2001. (4) J.R. Zanchetta, et al. Effects of ly333334 (recombinant parathyroid hormone ((1-34))) on cortical bone strength indices as assessed by peripheral quantitative computed tomography Abstract OR66 Presented at the International Bone Mineral Society Meeting. June 2001. (5) H. Pols et al. (presented by J.Y. Reginster.) Early onset and sustained efficacy of raloxifene on incident vertebral fractures in postmenopausal women with osteoporosis: 4-year results from the more trial. Abstract OR64 Presented at the International Bone Mineral Society Meeting. June 2001. (6) R. Eastell et al. J Bone Mineral Res. 2000; 15: (Supp 1):p S229. (7) N. Watts et al. Validation of change in bone mineral density as a surrogate for fracture risk after statistical adjustment for imprecision in BMD measurements. Abstract SC13T Presented at the International Bone Mineral Society Meeting. June 2001. (8) M. Maricic et al. Arthritis Rheum. 2000; 43 (Supp 9):S197. (9) R. Neer et al. NEJM. 10 May 2001; 344:19; 1434-41.