Clinical Development in Osteoporosis: A Case History
This report was reviewed for medical and scientific accuracy by Michael Divon, MD , Director of OB/GYN, Lenox Hill Hospital, New York.
New drug development has become more than a creative endeavor-it requires pharmaceutical companies to meet the challenge of transforming basic science into viable clinical applications. Today, the scientific aspects of successfully bringing a new medication to market rely heavily on how well the drug conforms to regulatory guidelines "without borders," for not only must the United States Food and Drug Administration be satisfied, but various other licensing agencies around the world need to be accommodated as well.
The development of such truly "world-class" medications was the theme of a drug development symposium held during the 22nd Annual Meeting of the American Society for Bone and Mineral Research. Centerpiece of the session was a presentation by Dr. Willard Dere, Executive Director, Global Clinical Research (Program Phase), Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana, who used the example of raloxifene hydrochloride (Evista®) to illustrate how his company blended preclinical science, marketing, and peer-reviewed, multi-national clinical trials to successfully launch this new class of bone-sparing drug into the global market.
Approved by the FDA for the prevention of osteoporosis in postmenopausal women in 1997, raloxifene hydrochloride is a selective estrogen receptor modulator (SERM) that protects against progressive thinning of bone mass and subsequent reduced bone strength. Although males and females alike can develop osteoporosis, the condition most commonly affects postmenopausal women, often leading to hip, wrist, or spine fractures.
As a SERM, raloxifene hydrochloride has been shown to have anti-estrogenic effects on breast and endometrial tissues, thereby reducing the risks for breast and uterine cancer, while simultaneously exerting beneficial estrogenic effects on bone, lipid metabolism, and blood clotting.
In discussing how Lilly developed and ultimately demonstrated the clinical benefits of ralraloxifene hydrochloride in clinical trials, Dr. Dere pointed out that global regulatory interactions were of key importance to the scientific process. "Not only did we need to consider draft guidelines from the FDA," he said, "but it was crucial to also take into account guidelines promulgated by the European Medicines Agency, the World Health Organization, the Ministry of Health and Welfare in Japan, and the European Working Group for Respect and Ethics and Excellence in Science (GREES).
"But today," he added, "a research physician who is involved in clinical trials must be cognizant of a number of other things as well. Our raloxifene development strategy had to proceed with close, on-going collaboration between the discovery, clinical, marketing, and regulatory departments at Lilly, among other areas. Product labeling was an extremely important aspect of our development plan, for instance, because you ultimately need to communicate a large body of information about the molecule. Dose findings, dose selection, and pharmacokinetics are also of crucial importance in the work that we do, as is deep analysis of the pre-clinical work involving in-vitro and in-vivo models. In fact, we referred to these models throughout the entire development plan, up to and during the clinical trials that we published in peer-reviewed scientific publications."
In fact, work in rodent and rabbit models was essential in enabling the researchers to assess the effects of raloxifene hydrochloride on bone quality and strength prior to entering a clinical setting, he confirmed. "The guidelines stipulated by the FDA and the other regulatory agencies said any drug used to treat or prevent osteoporosis must be shown to preserve or increase bone density and maintain bone quality-thereby showing it has the ability to reduce fracture rates," Dr. Dere said, "so this became central to raloxifene development-we had to ensure that we had estrogen-like activity in the skeleton."
Early in-vitro work comparing raloxifene hydrochloride and estradiol indeed showed that raloxifene hydrochloride works as an agonist in bone, but as an antagonist in other sites-notably the breast and the uterus. "This was the one aspect of the pre-clinical work that was mandatory for the ultimate success of our registration," he said.
Reviewing bone-marker research in rodents (Frolik et al., Bone,1996; 18(6):621-7) and rabbit studies that looked at aortic cholesterol content (Bjarnason et al., Circulation 1997; 96(6):1964-9), Dr. Dere said the major findings clearly showed raloxifene hydrochloride decreased aortic cholesterol content, produced a comparable effect with estradiol on bone strength, and confirmed that the drug works as an estrogen receptor antagonist in the uterus and the breast. "These preclinical studies also confirmed that the agent mimics the effects of estrogen on deep brain structures, such as brain-derived neurotrophic factor and nerve growth factor receptors," he added.
Lilly continued to build a case for the efficacy of raloxifene hydrochloride with Phase I pharmacokinetic studies that showed the agent could be given once daily and was well-tolerated, he said, which led to a Phase II controlled trial (Draper et al., J Bone Miner Res,1996; 11(6):835-42). This study demonstrated that raloxifene hydrochloride (200 mg per day or 600 mg per day) decreased biochemical markers of bone turnover; significantly decreased serum lipids, and had no stimulatory effects on the endometrium.
Then came three large, full-protocol, Phase III prevention trials involving approximately 1,800 post-menopausal women in Europe and North America, he said. Two of the studies demonstrated raloxifene hydrochloride increased bone mineral density (BMD) in the hip, spine, and total body, as compared to a calcium and vitamin D supplemented placebo group-results which validated Lilly's prevention claim for the raloxifene molecule.
The third study, "Effects of Raloxifene on Bone Mineral Density, Serum Cholesterol Concentrations, and Uterine Endometrium in Postmenopausal Women," published by Dr. Pierre Delmas and colleagues in the New England Journal of Medicine in December of 1997 (337; 23:1641-7), provided the seminal article that established raloxifene hydrochloride as a prevention for osteoporosis, Dr. Dere added-one that, unlike long-term estrogen therapy, could reduce osteoporotic fracture and cardiovascular disease without undesirable stimulation of breast and endometrial tissue.
In the two-year study, researchers examined the effects of raloxifene hydrochloride on bone mineral density, serum lipid concentrations, and endometrial thickness in 601 postmenopausal women, each of whom was randomly assigned to either 30, 60, or 150 mg of the drug or placebo daily for 24 months. Results showed women receiving any dose of raloxifene hydrochloride had significant BMD increases from baseline values in the lumbar spine, hip, and total body. By comparison, BMD decreased in the placebo group.
The investigators reported that at 24 months, the mean difference in BMD changes among women receiving 60 mg per day of raloxifene hydrochloride and those receiving placebo was 2.4 versus 0.4 percent for the lumbar spine; 2.4 versus 0.4 percent for the total hip, and 2.0 versus 0.4 percent for the total body (p < 0.001 for all comparisons). Serum concentrations of total cholesterol and low-density lipoprotein cholesterol decreased in all raloxifene hydrochloride groups, whereas serum concentrations of high-density lipoprotein cholesterol and triglycerides went unchanged. Endometrial thickness was reported as similar in the raloxifene hydrochloride and placebo groups at all times during the study, with no difference between groups in the number of women reporting hot flashes or vaginal bleeding. The researchers concluded that daily therapy with raloxifene hydrochloride increases bone mineral density; lowers serum concentrations of total and low-density lipoprotein cholesterol, and does not stimulate the endometrium.
Dr. Dere concluded his presentation by reviewing data from the Multiple Outcomes of Raloxifene Evaluation (MORE) trial (Ettinger B. et al., JAMA 1999; 282:637-45), a three-year efficacy study in which investigators examined the ability of raloxifene hydrochloride to reduce vertebral and non-vertebral fracture risks in postmenopausal women with osteoporosis.
MORE was a multi-center, randomized, blinded, placebo-controlled trial involving a total of 7,705 women, ages 31 to 80 years, in 25 countries. At study entry, all participants had been post-menopausal for at least two years and met World Health Organization criteria for having osteoporosis. Begun in 1994, the study was published with up to 36 months of follow-up for primary efficacy measurements and non-serious adverse events and with up to 40 months of follow-up for serious adverse events.
Participants were randomized to either 60 mg or 120 mg of raloxifene hydrochloride daily or to placebo. All participants received supplemental calcium and fat-soluble vitamin D.
The incident of vertebral fractures was determined radiographically at baseline and at scheduled 24- and 36-month visits, with non-vertebral fractures ascertained by interview at six-month interim visits. Bone mineral density was determined annually by dual-energy, X-ray absorptiometry.
At 36 months, radiographs showed 7.4 percent had at least one new vertebral fracture. This number was comprised of 10.1 percent of women receiving placebo, 6.6 percent of women receiving 60 mg per day of raloxifene hydrochloride, and 5.4 percent of women receiving 120 mg per day of raloxifene hydrochloride. Vertebral fracture risk was reduced in both study groups receiving raloxifene hydrochloride. For the 60 mg dosage group, relative risk [RR] was 0.7 (95 percent confidence interval [CI], 0.5-0.8). For the 120 mg dosage group, RR was 0.5 (95 percent CI, 0.4-0.7).
Risk of non-vertebral fracture for the raloxifene hydrochloride groups did not differ significantly (RR, 0.9; 95 percent CI, 0.8-1.1) for both raloxifene hydrochloride groups combined. Compared with placebo, however, raloxifene hydrochloride increased BMD in the femoral neck by 2.1 percent (60 mg) and 2.4 percent (120 mg), and by 2.6 percent (60 mg) and 2.7 percent (120 mg) in the spine (p < 0.001 for all comparisons). In addition, women receiving raloxifene hydrochloride had increased risk of venous thromboembolism compared to women receiving placebo (RR, 3.1; 95 percent CI, 1.5-6.2), similar to that seen with hormone replacement therapy. However, raloxifene hydrochloride did not cause vaginal bleeding or breast pain and was associated with a lower incidence of breast cancer.
Investigators concluded that in post-menopausal women with osteoporosis, raloxifene hydrochloride increases bone mineral density in the spine and femoral neck and reduces risk of vertebral fracture. "If you examine the fracture outcomes seen in the MORE study closely," Dr. Dere added, "the essential findings show about a 55 percent reduction in the incidence of vertebral fractures in patients who were osteoporotic but had no pre-existing fractures, and a 30 percent reduction in vertebral fractures in women who did have pre-existing fractures." Further, the BMD increases seen in a sub-group of participants, who were at least age 67 at study entry, show beneficial changes similar to those seen in the prevention studies-about a two to three percent increase compared to the calcium (500 mg per day) and vitamin D (500 IUs per day) supplemented placebo group.