Evista: Clinical Trial Results Question Its Safety and Efficacy

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Evista: Clinical Trial Results Question Its Safety and Efficacy

By Lucy Sannes, Ph.D., Sannes & Associates
Vicki Glaser, Contributing Editor to Pharma DD, contributed to this article.

November 2, 2006

Results of the RUTH (Raloxifene Use for the Heart) trial, published in July 2006, linked Eli Lilly’s Evista (raloxifene) with an increased risk of venous embolism (blood clots) and fatal stroke. Additionally, Evista did not reduce a woman’s risk of coronary events such as heart attack. The drug received U.S. FDA approval in 1999 for the prevention and treatment of osteoporosis in postmenopausal women. On a more positive note, The RUTH trial results demonstrated that Evista can significantly decrease invasive breast cancer risk, especially the estrogen-positive variety.¹These results add another dimension to the continuing debate over how to weigh the benefit of risk reduction for breast cancer versus the increased risks of potentially fatal side effects with Evista use.

Evista has proven to be a blockbuster drug for Lilly in the area of osteoporosis prevention and treatment. In 2004, combined sales of drugs to treat osteoporosis reached an estimated $6.2 billion in the seven major markets.² In 2005, worldwide sales of Evista were $1.04 billion; U.S. sales accounted for $653 million of that total. FDA approval of Evista for the additional indication of breast cancer reduction would likely boost Lilly's sales even further.

Evista is a member of the class of drugs known as selective estrogen-receptor molecules (SERMs). The considerable interest surrounding this class of drugs focuses on their ability to act as estrogen agonists in some tissues and as estrogen antagonists in other tissues. As a result, SERMs offer the benefits associated with estrogens on bones (and on lipid levels in the blood), but do not appear to have the negative effects associated with estrogens in breast and endometrial tissues.

Tamoxifen, the first SERM to reach the market in the U.S. , received initial FDA approval in late 1977 for the treatment of breast cancer. Subsequently, in 1998, approval was added for prevention of breast cancer in women at high risk. Tamoxifen is, however, associated with an increased risk of endometrial cancer and of blood clots and stroke. This risk profile fueled efforts to develop newer SERMs, including Evista.

In June 2006, one month before publication of the RUTH trial results, findings of the STAR (Study of Tamoxifen and Raloxifene) study were published. This study, which included 19,747 postmenopausal women with increased risk of breast cancer, showed that raloxifene (Evista) was more effective than tamoxifen in reducing a woman’s risk of breast cancer.^{3,
4}

Previously, in April 2006, Eli Lilly announced preliminary results from the RUTH trial, which included 10,101 postmenopausal women with coronary heart disease (CHD) or with risk factors for CHD. A few days later, the National Cancer Institute (NCI) made public preliminary results of the STAR trial. Later that month, when Eli Lilly released its first-quarter results, the company projected—based on data from these and earlier trials—that Eli Lilly would submit a supplemental New Drug Application for Evista by the end of 2006, seeking approval for use in breast cancer risk reduction.

At this time, however, the fate of Evista for prevention of breast cancer is not clear. Eli Lilly has not commented further on its plans for Evista for reduction of breast cancer risk. The authors of the RUTH study report concluded that when clinicians consider prescribing Evista for postmenopausal women, they should take into account disease risk, potential benefits of treatment, personal preferences, and the availability of alternative therapies.¹

Competition Heats Up

Meanwhile, Evista is facing growing competition for its approved osteoporosis indications. Safety concerns about increased risk of blood clots and fatal strokes may further increase the pressure on Evista. Even before the publication of the STAR and RUTH trial results, worldwide sales of Evista during the first half of 2006 increased only 1% compared to the previous year, although second-quarter worldwide sales were up 5% compared to second quarter of 2005.

For several years, Evista has faced competition from hormone replacement therapy, calcitonin, and two bisphosphonates, Fosamax (alendronate) and Actonel (risedronate). In 2002, the FDA approved Eli Lilly’s Forteo (teriparatide), a recombinant form of parathyroid hormone delivered by injection. Roche’s Boniva (ibandromate sodium) was first approved in 2003 and, in March 2005, the FDA approved a monthly tablet form of the drug. Boniva is a bisphosphonate compound co-promoted by GlaxoSmithKline. The osteoporosis market became even more competitive in January 2006, when the FDA approved an intravenous formulation of Boniva that is administered only once every three months.

The market for drugs to prevent and treat osteoporosis will likely become even more competitive in the near future as additional agents are in late stage development (see Table). These include additional members of the currently available drug classes (bisphosphonates, SERMs, and parathyroid hormone). It is interesting to note that Eli Lilly is developing a second-generation SERM (arzoxifene) that the company reports has greater potency and bioavailability than Evista. In addition, Chugai’s ED-71, a vitamin D derivative, is in Phase III development in Japan.

Selected Late-Stage Therapies in Development for Prevention and/or Treatment of Osteoporosis

Company	Product/Technology	Status	Comments
Amgen	denosumab (formerly called AMG 162)	Phase III	•Fully human monoclonal antibody that targets the receptor activator of nuclear factor kappa B ligand (RANKL), a mediator of bone resorption •Also being evaluated for rheumatoid arthritis, bone metastases in breast cancer, prolongation of bone metastases-free survival, and for bone loss resulting from hormone ablation therapy for breast or prostate cancer
Chugai Pharmaceutical ( Japan )	ED-71	Phase III	•Orally available Vitamin D3 derivative •For osteoporosis
Eli Lilly	arzoxifene	Phase III	•Next-generation selective estrogen receptor modulator (SERM) • For prevention and treatment of osteoporosis in postmenopausal women, and for risk reduction of breast cancer in postmenopausal women •Lilly reports that arzoxifene has greater potency and bioavailability than Evista
Novartis	Aclasta (zoledronic acid 5 mg solution; for infusion)	Phase III (osteoporosis)	•A once-yearly treatment for osteoporosis •An intravenous bisphosphonate •Approved for treatment of Paget’s disease in over 40 countries •Submitted for approval in the US for Paget’s disease •Submission for osteoporosis in the US and EU planned for 2007
NPS Pharmaceuticals	PREOS (parathyroid hormone (rDNA origin; for injection)	Submitted to FDA	•FDA New Drug Application submitted May 2005 •Licensed to Nycomed for development and marketing in Europe; in May 2006, NPS announced that the European Commission had granted marketing authorization for Preotact, the European brand name for PREOS
Pfizer	Oporia (lasofoxifene)	Received non-approvable letters from FDA	•Sept. 2005: Non-approvable letter from FDA for prevention of post-menopausal osteoporosis •Jan. 2006: Non-approvable letter from FDA for treatment of vaginal atrophy •2005 company financial report states that Pfizer “is currently in discussions with the FDA regarding these 'non-approvable' letters and we continue to develop both of these compounds” [referring to lasofoxifene and another compound also not approved by the FDA].
Wyeth	bazedoxifene	NDA filed 2^nd quarter 2006	•SERM; for postmenopausal osteoporosis
Wyeth	bazedoxifene/ conjugated estrogens	Phase III	• SERM combined with conjugated estrogens; for postmenopausal osteoporosis and for vasomotor symptoms of menopause

Source: Sannes & Associates

In the United States, Evista may also face competition from a completely new type of drug being developed by Amgen. Denosumab is a fully human monoclonal antibody that targets the receptor activator of nuclear factor kappa B ligand (RANKL), a mediator of bone resorption. The drug is in Phase III development for postmenopausal osteoporosis and is also being evaluated in clinical trials for other bone-related conditions. In February 2006, Amgen announced the publication of data from a Phase II trial in which twice-yearly injections of denosumab significantly increased bone mineral density at multiple locations compared to placebo.

Evista is facing increasing market pressure, and this will become even greater with the new questions regarding increased risk of blood clots and fatal strokes. In addition, Evista is facing competition from newer therapies that offer the convenience of less frequent dosing, perhaps only two to four times a year, compared to the daily dosing required with Evista. In the future, the osteoporosis market may prove to be a challenging arena for Eli Lilly.

References

1. Barret-Connor E, Mosca L, Collins P, et al. Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. N Engl J Med 2006;355(2):125–137.

2. Decision Resources, Inc. The Expanding Osteoporosis Market: Potential of Current and New Drugs. September 29, 2005. Available at http://www.researchandmarkets.com/reportinfo.asp?report_id=314845.

3. Vogel VG, Constantino JP, Wickerham DL, et al. Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: The NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA 2006;295(23):2727–2741.

4. Land SR Wickerham DL, Constantino JP, et al. Patient-reported symptoms and quality of life during treatment with tamoxifen or raloxifene for breast cancer prevention: The NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA 2006;295(23):2742–2949.