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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.1 These 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
|
|
NDA
filed 2nd 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.
Copyright 2006, All Rights Reserved. Cambridge
Healthtech Institute.
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