P2, Bloomberg just came out with a transcript of an interview between CNBC's Peter Schecknower (sp?) and Robinson just before the Robertson Stephen's talk. I have only heard the transcript, but a few new things did come out. I'll give details later, but Robinson said that LGND now had 3 SERMs in the clinic. I don't think that he was counting Evista because LGND doesn't get royalties on sales although one of the research programs will look at combination therapy between Evista and Targretin. The only two other compounds are PFE's Droloxifene and CP366,156, so Robinson's comments may indicate that AHP's TSE424 has already entered the clinic. I expect a LGND press release, but I'm not sure if it will be this year or early next year (LGND has said that they expect TSE424 to enter the clinic in 1Q,'98 and it was mentioned in the Boston Globe:
Alternative to estrogen may get ok
(By Judy Foreman, Globe Staff, November 17, 1997)
For more than 50 years now, there has been only one drug around to
combat the immediate and longer-term effects of menopause: estrogen.
The plusses of estrogen are extraordinary -- reduced hot flashes, less vaginal
dryness, lower levels of ''bad'' and higher levels of ''good'' cholsterol,
reduced risk of osteoporosis, cardiovascular disease and maybe even
Alzheimer's. Not to mention better mood and intellectual function, at least for
some women.
But the minus is a frightening one: a possible 30 to 40 percent increase in the
risk of breast cancer. That's not huge if you're at normal risk to start with, but
it's big enough that many women say ''No, thanks,'' even though the lifetime
risk of dying of cardiovascular disease is six times higher than the risk of
dying of breast cancer.
At long last, there may soon be an option for women trying to juggle the risks
and benefits of estrogen therapy. It's called raloxifene, the first of the
''designer estrogens'' that manufacturers are racing to bring to market.
On Thursday, an advisory panel of the US Food and Drug Administration
will consider whether to recommend approval of raloxifene as a way to
prevent one post-menopausal problem, osteoporosis. If it passes that hurdle,
the FDA will probably approve it for marketing soon.
But like Premarin -- the 40-cents a day pill used by most American women
who take estrogen supplements -- raloxifene, whose price has not yet been
set, falls well short of the ideal.
The big advantage, researchers say, is that it seems not to stimulate breast
tissue, as estrogen does. In fact, if early studies are correct, raloxifene may
actually lower the risk of breast cancer.
That's probably because, like its chemical cousin tamoxifen, which is already
being marketed to treat breast cancer and is being studied as a way to
prevent it in high risk women, raloxifene acts like estrogen in some tissues,
but in others like an estrogen blocker. Estrogen is known to promote some
breast tumors.
Moreover, unlike both estrogen and tamoxifen, raloxifene does not seem to
stimulate uterine tissue, which means it does not cause bleeding and may not
raise the risk of uterine cancer. (To offset the increased risk among women
taking estrogen, doctors often prescribe another hormone, progesterone.)
Like estrogen, raloxifene also prevents bone loss, though not as powerfully.
In studies of 12,000 women in 25 countries, raloxifene increased bone
mineral density by 2 to 3 percent, according to Eli Lilly, the manufacturer,
though it's too soon to tell whether this translates into fewer broken bones.
The big drawback to raloxifene is that it does nothing for hot flashes, the
main reason many women start taking estrogen around age 50. In some
women, raloxifene actually triggers them. It also does nothing to combat
vaginal dryness and doesn't boost good cholesterol as much as estrogen.
Perhaps most important, raloxifene has only been studied for three years,
versus decades for Premarin, which is made by Wyeth-Ayerst.
''Many view this as a wonder drug,'' says Dr. Nananda Col, an internist at
New England Medical Center who has analyzed the risks and benefits of
estrogen. ''But I am very cautious.''
Raloxifene ''has a lot of promise, but we don't have concrete information on
long-term risks and benefits,'' she says, adding that some drugs initially
thought to be safe, like the fen-phen diet pills, later turn out not to be.
On the other hand, it's progress ''just to have any alternative to estrogen,''
says Dr. Bruce Kessel, a reproductive endocrinologist at Beth Israel
Deaconess Medical Center who also advocates diet and exercise to keep
the heart and bones healthy.
Dr. Isaac Schiff, chief of obstetrics and gynecology at Massachusetts
General Hospital, agrees. ''I believe this is a big step forward, but it's not
necessarily going to be the last agent we come to,'' he says.
Currently, Pfizer Inc. is working on one new drug called droxolifene,
Wyeth-Ayerst on something they call TSE-424, and SmithKline Beecham on
idoxifene.
As with all designer estrogens -- or SERMS, selective estrogen receptor
modulators -- the goal is to concoct a drug that prevents hot flashes, vaginal
dryness, osteoporosis, heart disease, and possibly Alzheimer's, but does not
raise breast cancer risk. Unfortunately, nothing in the pipeline so far can do
all this.
And because raloxifene, to be marketed under the name EVISTA, does not
reduce hot flashes, estrogen will likely remain the drug of choice for women
in the immediate throes of menopause.
''Raloxifene isn't a substitute for estrogen for menopausal symptoms. That's
not what this is all about,'' says V. Craig Jordan, director of breast cancer
research programs at the Robert H. Lurie Cancer Center at Northwestern
University Medical School in Chicago and a consultant to Eli Lilly.
But after a few months or years on estrogen, when hot flashes naturally abate
and the reason for taking estrogen becomes prevention of heart disease and
osteoporosis, it might make sense to switch to raloxifene, says Kessel, who
is about to start a study on the new drug.
''If you're taking estrogen for osteoporosis and you're concerned about
breast cancer, I would make the switch,'' adds Schiff in Boston, though he
notes that women should always taper off estrogen slowly and under a
doctor's supervision.
And raloxifene ''would be a good initial choice for a woman who has no hot
flashes and is concerned about osteoporosis,'' says Dr. Ethel Siris, a
raloxifene investigator for Eli Lilly and director of the osteoporosis program
at Columbia Presbyterian Medical Center in New York.
Another option for such women, she and others note, is Fosamax, an already
approved drug that prevents osteoporosis but has none of the other risks or
benefits of estrogen.
What has people most excited about raloxifene is its apparent lack of effect
on breast tissue.
''It is clear that you don't stimulate breast cell growth with raloxifene,'' Siris
says, adding that preliminary data suggest there may even be ''a decreased
risk of breast cancer, but we don't want to overly excite people.''
In fact, when Jordan, the Chicago researcher, studied the mammograms of
thousands of women taking raloxifene or a placebo in research studies, he
found ''about half as many women develop breast cancer on raloxifene as on
placebo over a two-year period.''
Jordan and other researchers caution that longer studies are needed. With
estrogen, for instance, the increased risk of breast cancer shows up only
after five or more years of use.
Another unanswered question is what effect raloxifene and its chemical
cousins may have on the brain. Some scientists hypothesize that estrogen has
a positive effect, which might be why women on estrogen may be less
susceptible to Alzheimer's disease. If raloxifene acts as an anti-estrogen (or
estrogen blocker) in the brain as it does in the breast, it would theoretically
have no such protective effect.
Figuring out precisely why the same drug boosts estrogen in some tissues yet
blocks it in others is big puzzle itself, especially now that scientists know
there are at least two distinct types of estrogen receptors, molecules in cells
with which estrogen and estrogen-like drugs interact.
But many researchers believe that even before all these answers are in, many
women may turn to raloxifen if it gets FDA approval.
That would be good news for women. And there might even be a silver lining
for Wyeth-Ayerst, which makes more than $1 billion a year worldwide
selling Premarin, until now without competition.
''Raloxifene will have a niche,'' according to the company's party line, ''but it
will not replace Premarin. It will broaden the market.''
SIDEBAR
More choice on the horizon
A federal Food and Drug Administration panel is meeting this week to
consider data on a new drug, raloxifene, for post-menopausal women. This
''designer estrogen'' and others like it in the pipeline may offer some of the
benefits of estrogen with fewer side effects.
Effects Raloxifene Estrogen
Bone
Density
2-3% increase in bone mineral density
4-5% increase in bone density
Fractures
No data yet
60% reduction in hip, spinal, wrist fractures
Cardio-vascular factors
LDL (bad cholesterol)
Reduces
Reduces
HDL (good cholesterol)
Little effect
Increases
Triglycerides
No effect
Increases
Coronary heart disease risk
No data yet
Probable benefit
Menopausal symptoms
Hot flashes
Modestly increases
Prevents
Cognitive function
No data yet
Possible benefit
Mood
No data yet
May improve (but can be offset by synthetic progesterone)
Vaginal dryness
No change
Prevents
Alzheimer's disease
Prevention
No data yet
Possible benefit
Risk of cancer
Uterine cancer
No data yet
Raises risk
Breast cancer
May decrease
May increase
Bleeding
Irregular bleeding
None
May cause
SOURCES: Craig Jordan, Northwestern University; Dr. Bruce Kessel, Beth
Israel Deaconess Medical Center
Globe staff chart
Previous ''Health Sense'' column are available through the Globe Online
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