Drug Pipeline Series: Phase III Oct23-Oct30, 2006

NICOX REPORTS RESULTS FROM OSTEOARTHRITIS TRIAL
NicOx has announced results from a successful Phase III trial for naproxcinod (HCT 3012) in patients with osteoarthritis of the knee (the 301 study). Both doses of naproxcinod were shown to be superior to placebo on all three co-primary efficacy endpoints of the study. Blood pressure data for both naproxcinod doses showed a sustained reduction versus baseline and naproxen at all time points, confirming earlier published clinical data. Naproxcinod is the first compound in the COX-inhibiting nitric oxide-donating class.
In terms of the co-primary endpoints of the study, both of the naproxcinod doses (375 and 750 mg) were shown to be superior to placebo, with this being highly statistically significant in terms of the mean change from baseline at week 13 in the following scores: the WOMAC pain subscale, the WOMAC function subscale and patients' overall rating of disease status.
During the trial, patients' blood pressure was measured at each visit. Prespecified analyses of the difference between the blood pressure at baseline and the measurements at week two, six and 13, demonstrated that both naproxcinod 750 and 375 mg decreased systolic and diastolic blood pressure. This effect was sustained until the 13-week time point and clearly differentiated naproxcinod from naproxen.
Naproxcinod also showed good overall safety: 46.7 percent of the patients treated with naproxcinod 750 mg and 40.8 percent on naproxcinod 375 mg experienced at least one adverse event, compared to 56.4 percent on naproxen 500 mg and 38.7 percent on placebo. The number of serious adverse events was low and evenly spread among treatment groups. The number of adverse hypotensive events was low across all groups.

Titan Initiates Phase III Development Program for Probuphine® in the Treatment of Opioid Dependence
Titan Pharmaceuticals, Inc. announced the initiation of a randomized, double-blind, placebo-controlled, multi-center Phase III clinical study of Probuphine in the treatment of opioid dependence. The 150 patient study will evaluate the safety and effectiveness of treatment with Probuphine versus placebo in reducing opioid dependence over 24 weeks of treatment. This study is part of a registration directed program intended to obtain marketing approval of Probuphine for the treatment of opioid addiction in Europe and the U.S. The Phase III program includes additional clinical studies scheduled to begin in the first half of next year.
Probuphine is designed to provide continuous, long-term therapeutic levels of the drug buprenorphine, an approved agent for the treatment of opioid dependence. The Company believes that Probuphine has the potential to reduce limitations currently associated with daily oral buprenorphine therapy, including poor compliance, variable blood levels, morning withdrawal symptoms before each daily dose, and misdirection of drug.

Drug Pipeline Series: Phase II, Oct23-Oct30, 2006

OREXIGEN REPORTS RESULTS FROM STUDY OF OBESITY DRUG
Orexigen Therapeutics announced that Excalia, a combination of two centrally acting medications intended to provide and sustain clinically important weight loss, demonstrated significant weight loss in a six-month, double-blind, Phase IIa clinical study. The magnitude of weight reduction exceeded that seen with placebo. The findings showed that patients completing the blinded 24-week phase lost on average 9.2 percent of their weight from baseline using Excalia compared with an average of 0.4 percent weight loss from baseline for patients using placebo. The study results further demonstrate that weight loss continued through an additional 24-week open-label period, with Excalia patients achieving an average weight loss of 12 percent from baseline by 48 weeks.
Excalia is a proprietary combination of bupropion, a dopamine and norepinephrine reuptake inhibitor, plus zonisamide, an approved anticonvulsant medication. The company's preclinical research suggests that combining these two central nervous system drugs acts on a complex of neurons in the hypothalamus, the area of the brain contributing to the regulation of appetite, energy output and maintaining body weight. The compound was tested in a double-blind, placebo-controlled, randomized, proof-of-concept Phase II clinical study of 127 non-smokers with body mass indices (BMI's) between 30 and 40.

RENOVO REPORTS POSITIVE RESULTS FROM SCAR-REDUCTION TRIAL
Renovo has announced positive Phase II clinical trial results for its lead drug, Juvista, in a 12-month proof-of-concept study of scar reduction at split-thickness skin graft donor sites.
Juvista is a therapeutic application of human recombinant TGFß3, which has been shown in clinical trials to markedly improve subsequent scar appearance in the skin. The trial was a fully randomized, double-blind, placebo-controlled study designed to investigate the safety, tolerability, systemic exposure and anti-scarring potential of Juvista in split-thickness skin graft donor sites. Clinical assessment by plastic surgeons at 12 months following administration of Juvista demonstrated a statistically significant reduction in scarring compared with placebo and indicated a permanent regeneration of more normal skin. This trial demonstrates, for the first time, the efficacy of Juvista in the reduction of scarring in large open wounds whose margins are not approximated and sutured.
Juvista was effective given as an injection followed by topical application at the time of surgery and topical application one day later. The study was the first time Juvista has been administered to open wounds and is in contrast to previous trials in incisional wounds closed by suture or steri strips.
Development of a topical formulation of Juvista would offer the prospect of additional indications such as reducing scarring in split thickness skin graft donor sites, grafts and burns which are markets of high medical need. Juvista injection for closed wounds following incisions/excisions, however, remains Renovo's primary target market as this represents the vast majority of surgical procedures.

ViroPharma and Wyeth Initiate Dosing in Phase 2 Study of HCV-796 in Treatment Naive Patients and Non-Responders
ViroPharma Incorporated announced that patient dosing has commenced in a Phase 2 study of HCV-796, a unique orally dosed hepatitis C viral polymerase inhibitor that interferes with the replication of hepatitis C virus (HCV).
The Phase 2 study is being conducted with Wyeth Pharmaceuticals, a division of Wyeth (NYSE: WYE), ViroPharma's partner in development of HCV-796.

The objectives of this trial are to assess the safety, tolerability, pharmacokinetic profile, and antiviral activity of HCV-796, when used in combination with pegylated interferon alfa-2b plus ribavirin compared to the current standard of care in treatment-naive subjects with HCV genotype 1 infection and in patients with HCV genotype 1 infection who were non-responders to prior HCV therapy. The companies will add an additional dose or doses of HCV-796 to the trial to further elucidate the dose response.

MethylGene Initiates Phase I/II Combination Clinical Trial with its Proprietary HDAC Inhibitor, MGCD0103, and Gemzar'R' in Patients with Pancreatic Cancer
MethylGene Inc., along with its partner Pharmion Corporation, announced the initiation of a Phase I/II clinical trial (Trial 006) evaluating its isotype-specific histone deacetylase (HDAC) inhibitor product candidate, MGCD0103, in combination with Gemzar® (gemcitabine HC1; Eli Lilly and Company) in patients with solid tumors, including pancreatic cancer. Gemzar is an approved chemotherapy, marketed for use in pancreatic, non-small cell lung, breast and ovarian cancers.
In the Phase I portion of this open-label trial, MGCD0103 will be given orally, three times per week for four weeks in combination with Gemzar, which will be administered intravenously once per week for three weeks out of four in patients whose cancers are eligible to be treated with Gemzar, or patients who have no available standard of care. Key objectives for this portion of the study will be to evaluate the compatibility and safety of administering these two agents together, to determine the maximum tolerated dose of MGCD0103 and to define the Phase II dose to be administered in this combination. Secondary objectives include determining the dose-limiting toxicities, objective responses, time to progression, survival, and the pharmacodynamic and pharmacokinetic characteristics. In the expanded Phase II portion of the trial, the primary objective is to determine the overall response rate in pancreatic cancer patients. The trial may enroll up to 60 patients at cancer centers in North America. The trial is expected to take 18 to 24 months to complete.

EntreMed Commences Clinical Trial for MKC-1 in Lung Cancer Patients
EntreMed, Inc. announced commencement of a multi-center study with its drug candidate, MKC-1, in non-small cell lung cancer (NSCLC) patients. The lead institution for this Phase 1/2, open label, dose escalation study will be the Indiana University Cancer Center in Indianapolis, Indiana. Nasser H. Hanna, M.D., Assistant Professor, Department of Medicine, Division of Hematology/Oncology at IUCCI, will serve as Principal Investigator. MKC-1 is being evaluated currently in Phase 1 and 2 clinical studies against breast cancer and in patients with leukemia.

The objective of the Phase 1 portion of this study will be to assess the safety and maximum tolerated dose of MKC-1 when administered orally in combination with pemetrexed (Alimta®). Alimta® is a multi-targeted antifolate, which blocks the activity of folic acid and is approved for the treatment of metastatic NSCLC.
The Phase 2 component of this study will assess the antitumor activity and progression free survival (PFS) in up to 60 patients with non-small cell lung cancer. Patients whose disease has progressed following initial therapy may be eligible to enroll. Patients will receive orally administered MKC-1 in combination with pemetrexed (Alimta®). A secondary endpoint of the Phase 2 study will be to evaluate other parameters of antitumor activity including response duration and overall survival.
MKC-1 is a novel, orally active cell cycle inhibitor with in vitro and in vivo efficacy against a wide range of human solid tumor cell lines, including multi-drug resistant cell lines. MKC-1 has demonstrated broad-acting antitumor effects, showing tumor growth inhibition or regression in multiple animal models, including paclitaxel-resistant models. MKC-1 has been shown to inhibit mitotic spindle formation, prevent chromosome segregation in the M- phase (mitosis) of the cell cycle, and induce apoptosis. These effects are consistent with a mechanism resulting from MKC-1 binding to multiple intracellular targets, including tubulin and the importin beta proteins. The importin beta family of proteins plays a critical role in nuclear transport and cell division.

Neurogen Commences Phase II Clinical Trial in Chronic Insomnia Patients
Neurogen Corporation announced that it has commenced a Phase II clinical trial in chronic insomnia patients with the Company's insomnia agent, NG2-73. The study will measure reduction in time to onset of persistent sleep and sleep maintenance across a range of doses and formulations during two weeks of treatment. NG2-73 selectively modulates receptors of the gamma-aminobutyric acid (GABA) neurotransmitter system and is one of several unpartnered compounds in Neurogen's portfolio.
The Phase II clinical trial is a randomized, double-blind, placebo-controlled, multi-center, parallel group study designed to determine the efficacy and safety of five different dose and formulation profiles of NG2-73 compared to placebo. The primary endpoint will be the time it takes to fall asleep as defined by Latency to Persistent Sleep (LPS). Sleep maintenance will be explored in several secondary endpoints. At least 240 chronic insomniacs, aged up to 64 years, are expected to receive study drug or placebo for 14 days. Polysomnography will be used to measure various sleep parameters.

Drug Pipeline Series: Phase I, Oct23-Oct30, 2006

EPIX Pharmaceuticals Initiates Phase 1 Multiple Ascending Dose Clinical Trial of PRX-07034 in Obesity
EPIX Pharmaceuticals, Inc. announced the initiation of a Phase 1 multiple ascending dose clinical trial to study the safety, tolerability, pharmacokinetics, and pharmacodynamics of PRX-07034 administered once-daily for 28 days in a population of otherwise healthy obese adults with body mass indices between 30 and 42 kg/m(squared). PRX-07034 is a novel, highly selective 5-HT6 receptor antagonist being developed for the treatment of obesity, as well as for cognitive impairment associated with Alzheimer's Disease and schizophrenia.
PRX-07034 is a novel, highly selective, small-molecule antagonist of a specific G-protein coupled receptor (GPCR) known as 5-HT6. Preliminary safety and tolerability data from a recently completed single ascending dose Phase 1 trial in healthy adult male and female volunteers indicated that single doses of PRX-07034 were well-tolerated up to 2500 mg, the highest dose tested. In addition, PRX-07034 demonstrated adequate absorption, with drug exposures increasing with increasing doses and a half-life of 14 to 24 hours, making it suitable for once-daily dosing.

Metabasis Therapeutics Initiates a Phase 1 Clinical Trial of MB07811, a Novel Product Candidate for Reducing Both LDL-Cholesterol and Triglycerides
Metabasis Therapeutics, Inc. announced that it has initiated a Phase 1 clinical trial of MB07811, a novel, orally active product candidate for the management of hyperlipidemia, or elevated cholesterol. MB07811, Metabasis' fifth internally discovered product candidate to enter human clinical trials, uses the Company's proprietary HepDirect® prodrug technology to target a beta-subtype-selective thyroid hormone receptor (TRB) agonist to the liver to reduce serum cholesterol (LDL) and triglycerides (TGs). The Company believes that this drug class has the potential to be additive to the class of hyperlipidemia drugs known as "statins", and preclinical data suggests that MB07811 could be as effective at lowering serum cholesterol as this important drug class. Statins represent a drug class commonly used to treat hyperlipidemia and at present comprise the single largest pharmaceutical market in the world, growing by over 15% per year.
The study initiated will evaluate the safety and tolerability of MB07811 in a rising single dose study in healthy volunteers. Assuming the successful completion of additional preclinical trials and the recently initiated Phase 1 single dose trial, the Company expects to pursue further clinical studies, including a multiple dose Phase 1 study in healthy volunteers.

INNOVIVE Pharmaceuticals Begins Enrollment in Phase I Study of INNO-305 Peptide Immunotherapy in AML, MDS, Mesothelioma and Non-Small Cell Lung Cancer
INNOVIVE Pharmaceuticals, Inc. announced that a Phase I clinical trial investigating INNO-305 in acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), mesothelioma and non-small cell lung cancer (NSCLC) has enrolled its first patient. The trial is being conducted by Lee Krug, M.D., of the Thoracic Oncology Service, and Peter Maslak, M.D., of the Leukemia Service at Memorial Sloan Kettering Cancer Center in New York.
The study is an open label fixed dose trial and will study the safety, tolerability, pharmacokinetics and preliminary efficacy of INNO-305. The vaccine will be tested in patients with hematologic malignancies and solid tumors for which there is evidence of WT1 expression.
INNO-305, a WT1 peptide therapeutic vaccine, is unique among WT1 peptide immunotherapies because of its ability to stimulate both CD8 and CD4 T-cells. It is believed that stimulating both types of T-cells may result in a more robust and ubiquitous immune response. As an added measure, INNO-305 utilizes an approach in which the wild-type WT1 peptide sequences are altered to improve the ability of the drug to activate T-cells.

Anesiva Starts Phase 1 Clinical Study of 1207, New Topical Local Anesthetic
Anesiva, Inc. announced that it has commenced Phase 1 clinical testing of product candidate 1207, a new topical local anesthetic for the potential treatment of numerous pain conditions, including neuropathic pain.
The study, designed to assess the safety of 1207, will enroll 24 adult healthy male volunteers in up to six dose-escalating cohorts in Australia. In addition to safety data, the randomized, double-blind, placebo-controlled study will measure sensory perceptions of touch and warmth following a single topical administration of 1207 compared with placebo.
1207 is a new chemical entity with novel anesthetic properties that provide pain relief by binding to the fast sodium channel on neurons responsible for transmitting pain signals from nerve endings to the brain. Specifically, 1207 binds to the fast sodium channel on both A nerve fibers responsible for transmitting immediate "adaptive pain" signals and C nerve fibers responsible for transmitting longer-term, dull, aching throbbing pain signals. By interrupting the communication channel of both A fibers and C fibers, 1207 is designed to provide effective topical pain relief with a faster onset and longer duration of action than currently marketed pain products. In preclinical testing, topical administration of 1207 demonstrated a long duration of action and deep, rapid penetration. Other potential applications for 1207 include pre-procedural use in dermatological surgery and post-surgical incision pain.

Tanox Initiates Phase 1 Clinical Trial Evaluating TNX-650 for Treatment of Asthma
Tanox, Inc. has begun dosing a Phase 1 clinical trial of TNX-650, a humanized monoclonal antibody being evaluated as a potential treatment for moderate-to-severe asthma.
The trial is a randomized, double-blind, placebo-controlled, dose- escalation study of the safety, tolerability and pharmacokinetics of single doses of TNX-650 in healthy volunteers. A total of 32 subjects will be enrolled in four cohorts in the study, which is being conducted at a single site in the U.S.
TNX-650 targets Interleukin 13 (IL-13). Preclinical studies indicate that IL-13 is a key mediator of asthma responses, including airway inflammation, obstruction and hyper-reactivity. TNX-650, which has a mechanism of action unique from currently available asthma treatments, has the potential to be a therapeutic option for patients whose disease is not currently well controlled and for non-allergic asthmatics.

Researchers Seek Key To Antiaging

In the 1930s, researchers stumbled onto a surprisingly simple way to slow the biological forces of aging: cutting normal calorie intake by about a third. Scientists found it boosts animals' life spans by 30% to 40%, and considerable evidence suggests that calorie restriction, or CR, would slow human aging too.

But only steely ascetics could hack its hunger pangs. So the finding remained a little-known curiosity in the back halls of science.

Now a coterie of scientists and biotech ventures are rekindling interest in CR as they try to mimic its antiaging effects with medicines. It is still a highly speculative quest, and many researchers fret that it hasn't completely shaken its association with centuries of dubious nostrums to slow aging, from inhaling virgins' breath to eating gold to implanting monkey glands.

Much of the new focus is on a substance in red wine called resveratrol. The interest in it started three years ago when a group led by Harvard Medical School biologist David Sinclair reported that it boosted yeast cells' life span by 70% via a mechanism resembling CR. He later co-authored a study showing that it also boosts life span in fruit flies and roundworms. But his tendency to make bold leaps based on tentative data has also sparked intense controversy. One big question: Does he really understand the workings of CR well enough to mimic them in a drug?

Last spring, Italian scientists reported that resveratrol boosted life span more than 50% in a kind of short-lived fish. Intriguingly, fish on resveratrol had much faster swimming speeds as they aged, and spent far more time moving around, than did undosed control fish.

At least two groups of researchers are now testing whether resveratrol can extend life span in mice -- the first such studies in mammals. At a meeting of the American Aging Association in June, Dr. Sinclair and colleagues presented preliminary results from a study showing that resveratrol had "CR-like protective effects" against the buildup of fatty deposits in the livers of mice on high-calorie diets. That suggests that resveratrol could lead to new drugs for diseases of aging associated with rich diets, such as adult-onset diabetes.

A company that Dr. Sinclair co-founded in 2004, Sirtris Pharmaceuticals Inc., of Cambridge, Mass., has begun testing a resveratrol-based drug in diabetic patients. It has raised $82 million from venture capitalists, a hefty sum for an early-stage biotech. (Sirtris's chief executive, Christoph Westphal, is married to a reporter for this newspaper.)

It faces competition from Elixir Pharmaceuticals Inc., also based in Cambridge, which Dr. Sinclair's former mentor, Massachusetts Institute of Technology biologist Leonard Guarente, co-founded in 1999 to develop drugs based on gene variants that slow aging. The niche also includes BioMarker Pharmaceuticals of Campbell, Calif., and LifeGen Technologies of Madison, Wis., both of which focus on mimicking CR with drugs.

The companies hope to develop therapies for diseases, not antiaging pills. One reason is that the Food and Drug Administration doesn't recognize aging as a problem warranting treatment. But if a drug could retard aging, it might delay the onset and possibly the progression of age-related diseases. "When you slow aging," says University of Illinois epidemiologist S. Jay Olshansky, "you push a host of diseases to later ages at one fell swoop -- cancer, heart disease, Alzheimer's, diabetes, as well as everything else that's negative about growing older."

Some researchers believe antiaging drugs could also improve health in late life -- rather than prolong misery -- letting people stay in relatively good shape until a swift demise. Their case rests partly on the svelte, energetic look of old animals on CR. "Often it's hard to identify the cause of death" in post-mortem studies on such animals, says Richard Weindruch, a University of Wisconsin CR researcher. "The only apparent problem is that they died."

Still, some experts on aging doubt that enough is known about CR to guide the development of drugs that mimic its effects. "We know a lot about CR's effects," says Edward Masoro, a leading gerontologist. "But what bothers me is that I don't think we've figured out CR's basic mechanism yet."

Dr. Sinclair's idea that resveratrol mimics CR has come under heavy fire. His main adversaries are two researchers who used to rub elbows with him when they all studied together with MIT's Dr. Guarente. The skeptics maintain that resveratrol's mode of action is still murky; instead, they are looking at other mechanisms that may account for how CR works.

The resveratrol doses used in the life-span-extension studies in animals were far higher than the amount people can get by drinking wine -- they were roughly equivalent to hundreds of glasses a day. Resveratrol is available as a dietary supplement, but to replicate the doses used in the studies, a person would need to take scores of pills a day. (Sirtris says it is developing prescription drugs that work like resveratrol but are hundreds of times more potent.) The dietary supplements haven't been tested in clinical trials, so their efficacy isn't proven, nor is it clear what dose might make people live healthier or longer. And although they seem safe at modest doses, megadoses may not be.

Nevertheless Dr. Sinclair, a 37-year-old Australia native, thinks taking small doses over time may yield health benefits and has been taking the supplements for three years.

The story of resveratrol has its roots in scientists' increased understanding of CR. In 1989 researchers theorized that it activates a "starvation response" whose genetic machinery evolved eons ago to enable survival through periods of food shortage -- such as droughts -- by retarding the rate of aging. The response blocks growth and reproduction in order to free up energy to slow aging. The energy is siphoned to cellular systems that limit damage from harmful "free radical" molecules and other toxins produced as metabolic byproducts in cells.

The theory explained longstanding mysteries about CR, such as the fact that animals on CR become resistant to toxic chemicals and temporarily lose the ability to reproduce. It also had a dismaying implication: Our obesity-fostering, high-calorie diets are putting us in fast-aging-and-reproducing mode. That may be why childhood obesity is closely linked to early puberty, which now begins before age eight in many girls, and why adult obesity is linked to such a wide swath of aging diseases -- cancer, heart disease, diabetes, arthritis, even Alzheimer's.

But an important piece of CR's machinery remained hidden: the activator that senses calorie intake and, when it is low, triggers cellular changes that retard aging. This CR off-on switch is the holy grail of gerontology, the study of aging. In principle, drugs that turn it on could ward off or ameliorate degenerative diseases of aging, just as CR does in animals.

Many scientists are looking for the switch. And to the consternation of some of them, Dr. Guarente, 54, and Dr. Sinclair assert that they know what it is. Further, Dr. Sinclair's research indicates that resveratrol toggles it in order to slow aging. Their shared view on CR's basic mechanism has sparked a furious debate.

Its roots go back to 1991, when Dr. Guarente's lab at MIT began hunting for life-span-boosting mutations in baker's yeast.

The grandson of Italian immigrants, Dr. Guarente grew up in Revere, Mass., a blue-collar town near Boston. In his memoir "Ageless Quest," he recalls that as a child, "I was precocious by local standards -- I quit smoking in third grade."

By the mid-1990s, Dr. Guarente's lab had zeroed in on so-called SIR, or silent information regulator, genes. SIR mutations enabled yeast cells to divide an abnormally large number of times before dying, a form of extended life span. But how they worked wasn't clear until the group made further discoveries, one of which was Dr. Sinclair's first claim to fame.

Dr. Guarente recalls that Dr. Sinclair, who came to MIT in 1995 to do post-doctoral studies, breezed into his lab as if out of a Crocodile Dundee movie, greeting everyone with a cheery, "Hello, mate." The eldest son of parents who both worked in medical diagnostics, he was known in high school as a talented class clown and risk-taker, a kid who aced science classes but got in trouble for setting off minor explosions in chemistry lab. The idea of taking part in unorthodox, high-risk studies on aging suited him.

In a key experiment, Dr. Sinclair showed that yeast cells' machinery for copying chromosomes runs amok as the cells age, eventually killing them. Hailed as a major advance, the discovery got Dr. Guarente on Good Morning America. It also helped him formulate a theory positing that proteins made by SIR genes activate CR's antiaging action. A SIR gene found in mammals, dubbed SIRT1, seems especially important: It makes a protein that Drs. Guarente and Sinclair believe triggers the slowed-aging mode in mammals when calorie intake is low. In their view, it's either the gerontological grail or a crucial part of it -- hence, stimulating it might slow aging.

Drugs that juice up proteins' activity are very rare. But in 2003, Dr. Sinclair, then at Harvard, heard that scientists at Biomol International LP, a Plymouth Meeting, Pa., biotech firm, had observed signs of SIRT1 activation in test-tube experiments with certain plant compounds. The most promising one was resveratrol. That was doubly exciting, for dozens of studies on the red-wine ingredient had previously suggested that it lowered the risks of heart disease, cancer and various other disorders of aging -- just what a substance that slows aging should do.

Dr. Sinclair soon began the study about resveratrol's effects on yeast aging. But a year after it appeared, studies by other researchers cast doubt on the idea that SIR genes are key actuators of CR.

The sharpest questions were raised by two researchers who also studied under Dr. Guarente: University of Washington biologists Brian Kennedy and Matt Kaeberlein. Their data suggest that CR can exert antiaging effects independently of SIR genes, and that other genes are more central to CR -- at least in yeast. "My view is that CR probably has nothing to do" with SIR genes in lower animals, says Dr. Kaeberlein. In short, according to him, Drs. Guarente and Sinclair haven't necessarily found the grail.

Undaunted, Dr. Sinclair joined forces with a researcher at the National Institute on Aging, Rafael de Cabo, to plan one of the ongoing studies of resveratrol in mice. But he had a problem: He lacked the $20,000 needed to buy mice. Then he got a call out of the blue from Tom LoGiudice, foreman at the U4EA ("euphoria") Ranch near Thousand Oaks, Calif. Mr. LoGiudice had phoned on behalf of the ranch's owner, Harman Rasnow, who was considering taking resveratrol pills and wanted to know more about them. When Mr. LoGiudice heard about Dr. Sinclair's problem, he arranged for his boss to talk directly to the researcher. "I have an 85-year-old passion for longevity," says Mr. Rasnow, pinpointing his age. "David sounded like he was really onto something. So I told him, 'I'll send you a check for $20,000.'"

Dr. Sinclair later got another call from Mr. LoGiudice, this time inviting him to make a pitch for funding to one of Mr. Rasnow's wealthy acquaintances, Paul Glenn, a venture capitalist and a longtime supporter of research on aging. After Dr. Sinclair did so, the Glenn Foundation for Medical Research in Santa Barbara, Calif., awarded $5 million to Harvard Medical School to launch a center on the basic mechanisms of aging with Dr. Sinclair as its founding director. Now plans are afoot to expand the center into a leading institute on aging, says Mr. Glenn, with start-up funding of $75 million to $100 million.

Sirtris, the company Dr. Sinclair co-founded, says it has made progress. Test-tube and animal studies suggest that its early-stage drugs may help treat various neurological killers as well as diabetes, says Dr. Westphal. The company plans soon to begin testing a drug in people with MELAS syndrome, a rare metabolic disorder that afflicts youngsters with potentially fatal brain and muscle deterioration.

At a recent meeting on aging research, a Sirtris scientist reported that SIRT1-activating compounds, including resveratrol, dramatically lowered blood levels of glucose and insulin in mice that get diabetes on high-fat diets, as well as helped to keep their weight down -- just as CR does.

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Key antiaging medical advances: 1935: Cornell scientists report calorie restriction's antiaging effect in rodents. 1956: University of Nebraska researcher proposes that "free radicals" cause aging, indicating that antioxidants may slow it. 1989: U.S. and British scientists propose that calorie restriction triggers an evolutionarily ancient "starvation response" to slow aging. 1992: University of California at San Francisco researchers find a gene mutation that doubles life span in roundworms. 1996: Southern Illinois University scientists report gene mutation that extends life span in mice. 2000: MIT's Leonard Guarente and colleagues report that "SIR" genes actuate calorie restriction's antiaging effects in yeast. 2003: Harvard's David Sinclair and others report that resveratrol, a substance in red wine, extends yeast life span. February 2006: Italian scientists report resveratrol extends life span of a fish species.

6-Month Xience Diabetic Data Little-Changed

Abbott Laboratories Inc. (ABT) released more data for its Xience V drug-coated stent late Wednesday, showing very similar performance at six months in avoiding blood-vessel diameter changes with complex diabetic patients as with the other cases.

Other data in the Spirit II trial, meanwhile, showed no additional major heart problems in the six-to-nine-month timeframe.

Stents are tiny mesh tubes that prop open arteries, and drug-coated stents like Xience use medication to slow cell growth that can re-narrow arteries and lead to complications. Diabetic patients present more challenging stent cases, and also make up a sizable portion of stent recipients.

A subset of diabetic patients in the 300-patient Spirit II trial showed "nearly identical rates of in-stent late loss," or a measure of how vessel diameter changes at six months, Abbott said in a release. Abbott presented the latest Xience details at the Transcatheter Cardiovascular Therapeutics conference in Washington, D.C.

The Abbott Park, Ill., company garnered attention last month with the release of six-month data that showed Xience had better late-loss performance than Taxus, a popular stent made by industry giant Boston Scientific Corp. (BSX).

For diabetic patients in the trial, in-stent late loss was 0.15 millimeters for Xience versus 0.39 millimeters for Taxus at six months, Abbott said. This is comparable with the study's overall six-month results.

"We believe these results have the potential to differentiate Xience V for physicians with patients whose cases present more challenges for treatment," said John Capek, president of cardiac therapies in Abbott's vascular business, in the release.

The issue of stent safety has been a dominating topic at the cardiology conference. Specifically, talk and presentations have focused on the issue of late-stent thrombosis, or clots that form around a stent months or years after implantation.

Abbott said there were no additional cases of major adverse cardiac events or stent thrombosis in the Spirit II trial between six and nine months. In that time span, the major heart event rate stood at 2.8%, while the stent thrombosis rate stood at 0.5%, Abbott said.

Abbott significantly bolstered its stake in the stent sector through its April acquisition of Guidant Corp.'s vascular and endovascular business, a deal that included Xience. Abbott recently announced plans to drop its home-grown ZoMaxx drug-coated stent program amid poor data, but also just introduced the Xience in Europe slightly ahead of schedule.

Speaking during a conference with analysts on Monday, Capek said "the customer feedback has been remarkable" with Xience after just a few weeks on the market. He also said Abbott remains on track to introduce the stent in the U.S. in the first half of 2008 and in Japan in 2009, pending regulatory approval.

Xience data has bearing for Boston Scientific beyond the Taxus comparison, as Boston Scientific bought the bulk of Guidant through April's deal and agreed with Abbott to share rights to the Guidant stent program. Boston Scientific announced last week that it had received regulatory approval to market Promus, its version of Xience, in the European Union.

AstraZeneca Halts Development Of Key Drug

In a severe setback for a company that has stopped development of several drugs over the past two years, AstraZeneca Plc (AZN) said Thursday it's terminating development of its experimental stroke drug NXY-059 after it didn't reveal any benefit in a trial.

The drug failure leaves AstraZeneca, which is one of the world's biggest pharmaceutical companies, with only one potential blockbuster drug in late-stage development.

Lacking a significant number of drugs that will be able to compensate for declining sales once its bestsellers lose patent protection, AstraZeneca will now probably look even more aggressively for opportunities to buy the marketing rights to drugs developed by smaller companies, analysts said.

Speaking to reporters during a conference call, AstraZeneca Executive Director of Development John Patterson said the latest setback won't change the company's strategy of bolstering its pipeline through in licensing and acquisitions.

"We have made quite clear that we saw this as a high-risk project," Patterson told reporters.

Navid Malik, an analyst with London-based brokerage Collins Stewart, said that while AstraZeneca can maintain short-term growth by continuing its cost cutting strategy, "it desperately needs to bring new products to the market, without which no amount of cost cutting will help future earnings growth."

AstraZeneca shares slumped on the news. At 0832 GMT, they were down 4.5%, or 159 pence, at 3370p in a broadly higher London market.

Patterson said the study had proved that drugs like NXY-059, which aim to protect the patient's brain from further damage after a stroke, don't work.

"This is a sad day for patients with ischemic stroke, and a sad day for us," he said.

Analysts at Deutsche Bank AG had forecast peak sales of around $750 million for the drug, which was in an intermediate phase of development.

"The setback is likely to prompt investors to question the breadth and risk profile of the late-stage pipeline, as well as any impact the setback will have on AstraZeneca's in-licensing and mergers & acquisitions strategy," Deutsche Bank analysts said in a note to investors.

NXY-059 was licensed under a 15% royalty pact from Renovis Inc. (RNVS). AstraZeneca will now hand back the rights to the drug to Renovis, Patterson said.

Shares in Renovis, a biotech company headquartered in San Francisco, California, closed at $14.21 in New York Wednesday.

AstraZeneca is now left with a very thin pipeline after the recent expensive failures in late-stage testing of drugs such as blood-thinner Exanta, lung cancer drug Iressa and Galida for diabetes.

AstraZeneca's costs associated with discontinuing NXY-059 will be small at around $12.5 million, Patterson said.

Dropping the drug from the pipeline leaves AstraZeneca with just one other potential blockbuster in development: cardiovascular drug AGI-1067, which is in phase III testing, the latest step in development before a drug can be filed for regulatory approval.

Sanford Bernstein analyst Gbola Amusa said AstraZeneca's remaining key drug candidate will be now particularly important for sentiment.

The once-daily treatment for atherosclerosis, a build up of plaque and fat inside arteries, is expected to report results from current phase III trials in the first half of 2007.

AstraZeneca is due to post its third quarter earnings at 1000GMT Thursday.

Analysts expect the company to deliver a strong set of results, driven by key drugs Nexium, a heartburn treatment, and cholesterol-lowering treatment Crestor, which have seen strong prescription growth during the quarter, but also tight cost management.

AstraZeneca third-quarter operating profit is expected to advance 22% to $2.07 billion on sales rising 12% to $6.51 billion.

Company Web Site: http://www.astrazeneca.com

Panel OKs Shingles Vaccine For Elderly

For the first time in almost 30 years, a government panel is adding a vaccine, for shingles, to the list of preventive shots recommended for older adults against debilitating or life-threatening illnesses.

The Advisory Committee on Immunization Practices voted yesterday to recommend Merck & Co.'s new Zostavax vaccine for shingles in people over age 60. The committee of doctors and immunization experts convenes three times a year to shape vaccination policy for the Centers for Disease Control and Prevention, and its recommendations help determine both medical practice and insurance coverage policies.

Until now, the major vaccines recommended for older Americans have been to protect against flu and pneumonia.

The Food and Drug Administration approved Zostavax in May to prevent shingles, or herpes zoster, in patients over 60. Shingles emerges in people who have had chickenpox after the dormant virus reactivates in older adults. The virus causes pain and ultimately erupts on the skin as blisters and rash. About one million cases of shingles are reported annually in the U.S., of which 250,000 turn into more severe postherpetic neuralgia, or chronic nerve pain, according to Mark Feinberg, vice president for medical affairs and health policy in Merck's vaccine division.

The market -- and the CDC nod -- represents a boon for Merck, the only company selling a shingles vaccine, but the product won't necessarily be a blockbuster, analysts said. Zostavax had $11 million in third-quarter sales. With an estimated 50 million Americans over age 60 -- a population that stands to increase as baby boomers reach that age -- analysts estimate annual sales may approach $1 billion but more likely will top off around $600 million.

Unlike vaccines for school children, the shingles vaccine isn't required. "With seniors, there are questions about whether to go to the doctor, whether they want the vaccine," said Barbara Ryan, a pharmaceutical analyst at Deutsche Bank, who said she thinks the vaccine could potentially reach $400 million in U.S. sales. "There are a lot of reasons not everyone chooses to get vaccinated."

The one-dose, roughly $150 vaccine is a more potent version of Merck's chickenpox vaccine approved in 1995. In a large clinical trial, Zostavax reduced the incidence of shingles by 51% and the risk of long-term pain by two-thirds. The condition occurs most frequently in older people, yet Merck is testing Zostavax in younger age groups in hopes of expanding the market, Dr. Feinberg says.

"Shingles can be a pretty debilitating illness, and postherpetic neuralgia causes excruciating pain that has been very challenging to treat," said Sharon Brangman, a specialist in geriatric medicine at SUNY Upstate Medical University, in Syracuse, N.Y.

Dr. Brangman, a board member of the American Geriatrics Society, looks to the government recommendations to determine how to treat her roughly 3,000 elderly patients. Until now, though, she hasn't administered Zostavax, to be cautious with new medicines and mindful of how they may interact with the many treatments older patients tend to require.

"You don't want to give them something that makes it worse," she said.

Some health-care plans, such as Aetna Inc., began covering the vaccine when it came out. Others, such as Cigna Corp. and WellPoint Inc., are updating their plans based on the panel's recommendation. Merck estimated that plans covering 43% of insured patients reimbursed for the vaccine before the panel's recommendation. The vaccine costs $3 for so-called dual-eligible Medicare and Medicaid patients, while people in health plans may pay up to a 25% co-pay on the list price of about $150, Merck said.

FDA OKs Novartis' Drug For Chronic Hepatitis B

The U.S. Food and Drug Administration said Wednesday that it approved Novartis AG's (NVS) drug Tyzeka for the treatment of chronic hepatitis B.

The drug, a once-daily tablet, was developed by Idenix Pharmaceuticals Inc. (IDIX) with Novartis under a development and commercialization pact.

American depositary shares of Novartis, which is based in Switzerland, closed Wednesday at $60.74, up 42 cents, while shares of Cambridge, Mass.-based Idenix closed at $9.85, up 9 cents. In after-hours trading, Idenix rose 2% to $10.05 while Novartis was unchanged.

According to the FDA, a yearlong trial showed antiviral effectiveness of the drug, including the suppression of hepatitis B virus, and improvement in liver inflammation comparable to Epivir-HBV, one of five other medications approved to treat patients with the condition.

Novartis said in an email that in the phase III of the trial, 56% of all Tyzeka-treated patients achieved undetectable levels of the virus in the first 24 weeks of treatment. The virus remained undetectable at one year in 95% of those patients.

Chronic hepatitis B attacks the liver and can cause lifelong infection, scarring of the liver, and eventually liver cancer, liver failure and death.

The virus is spread when blood from an infected person enters the body of someone who isn't infected, sometimes by sexual contact or blood contamination.

An estimated 1.25 million Americans are currently infected with the virus, and 350 million people are infected worldwide. The disease is responsible for up to 1.2 million deaths each year, according to Novartis.

Side effects of the drug included upper respiratory tract infection, fatigue, headache, abdominal pain and cough, the FDA said.

In addition, after several weeks to months of Tyzeka use, some patients developed symptoms ranging from transient muscle pain to muscle weakness.

The agency also said that using Tyzeka hasn't been shown to reduce the risk of infecting others with hepatitis B.

Seeking Pain Pill Minus Gut, Heart Woes

Two drug companies hope to make a better arthritis drug with one pill that's a combination of a 30-year-old painkiller and a popular heartburn treatment. In the process they will seek to fill a void left when Vioxx was pulled from the market two years ago over safety concerns.

AstraZeneca PLC (AZN) of the U.K. and Pozen Inc. (POZN), Chapel Hill, N.C., recently formed a collaboration to develop a fixed-dose combination of naproxen, which is a generic pain reliever sold under the prescription brand Naprosyn and over-the-counter as Aleve, plus Nexium, AstraZeneca's blockbuster heartburn pill that racked up $4.6 billion in sales last year.

The companies plan to market the product as a treatment for pain associated with osteoarthritis and rheumatoid arthritis in people at risk for developing gastric ulcers caused by certain painkillers. Initially it would be a twice-a-day treatment, according to Pozen Chief Executive John Plachetka.

There are risks, however. As yet, there are no clinical data to prove the single-pill combination will work. And naproxen's label currently carries a warning that it can increase the risk of heart attack or stroke. A patient trial is expected to begin next year, and the drug is probably at least a couple of years away from reaching the market.

But the plan is to offer naproxen's pain relief while Nexium, known as a proton-pump inhibitor, alleviates some of naproxen's gastrointestinal side effects such as ulcers and bleeding.

"The idea is to produce a dosage form where the protectiveness of the product is released and deployed before" the gastrointestinal harm of naproxen occurs, Plachetka said in an interview.

Some arthritis specialists already prescribe naproxen and proton-pump inhibitors, or PPI's, to be taken together as separate pills. One company, Tap Pharmaceutical Products Inc., markets naproxen and the PPI Prevacid as separate pills in one package called Prevacid NapraPac. But Pozen and AstraZeneca believe a combination pill would be more convenient for patients and more effective in guarding against gastrointestinal problems.

If it works, Pozen and AstraZeneca think the single-pill combination could invade territory once dominated by a class of painkillers known as Cox-2 inhibitors. These drugs, including Merck & Co.'s (MRK) Vioxx and Pfizer Inc.'s (PFE) Celebrex, were designed to reduce the gastrointestinal side effects seen in older drugs like naproxen.

Merck's withdrawal of Vioxx from the market over safety concerns in 2004, however, raised questions about the cardiovascular risks of Cox-2 drugs. Merck said a study showed Vioxx elevated the risk of heart attack and stroke in people taking it for at least 18 months. In an earlier study involving both Vioxx and naproxen, there were five times as many heart attacks among those taking Vioxx as in the naproxen group.

A combination naproxen-Nexium could go after Celebrex, which remains on the market but with a warning on its label that it may cause an increased risk of heart attack and stroke. One government study found a two- to three-fold risk of heart attack, stroke or other cardiovascular events associated with Celebrex, compared with a fake pill, or placebo.

Another Cox-2, Pfizer's Bextra, also was withdrawn from the market last year over safety concerns. In 2004, the three main Cox-2 inhibitors - Vioxx, Celebrex and Bextra - had combined sales of more than $6 billion. But last year sales of Celebrex, the only Cox-2 left on the U.S. market, had fallen to $1.7 billion from $3.3 billion the year before.

Naproxen isn't free of concerns about cardiovascular safety, however, and while one study suggested it was safer on the heart than Vioxx, it's unclear whether naproxen is safer on the heart than Celebrex.

In late 2004, the National Institutes of Health said a study showed an apparent increase in risk for heart attacks, strokes or other cardiovascular events among people taking naproxen when compared to those on placebo. There was no significant increase in risk for Celebrex in the same NIH trial, which was designed to study whether the drugs could prevent Alzheimer's disease. NIH suspended use of both drugs in the trial, noting a separate study had raised questions about Celebrex's cardiovascular risk.

Still, some industry watchers believe naproxen is among the safest on the heart of all nonsteroidal anti-inflammatory drugs, or NSAID's, which include Cox-2's as well as older painkillers such as ibuprofen, sold under the brands Advil and Motrin, and diclofenac, sold as Voltaren.

"It's a smart idea," Steven Nissen, chairman of cardiovascular medicine at the Cleveland Clinic, said of the proposed naproxen-Nexium combination. "Naproxen, in all the studies, looks like it is very neutral from the point of view of cardiovascular risk.... However, it can be very hard on the stomach, and there is some data suggesting if you give a PPI that reduces stomach acid, it can reduce the risk of GI ulcer and bleeding."

Nissen is lead investigator of a large trial to study the relative heart safety of Celebrex, naproxen and ibuprofen. In the Pfizer-funded study, patients also are receiving a PPI to protect their gastrointestinal tracts, Nissen said, and the study will monitor gastrointestinal events.

David Graham, a drug-safety researcher for the Food and Drug Administration, recommended in the medical journal JAMA last month that generic naproxen plus a PPI would be less costly, equally as effective, and "probably safer" than low-dose Celebrex. He was referring to taking the drugs as separate pills.

Graham's JAMA editorial accompanied an analysis by other researchers suggesting naproxen didn't alter the risk of cardiovascular events; and that a lower dose of Celebrex didn't increase cardiovascular risk, but a higher dose appears to increase risk.

Gail Cawkwell, Pfizer's senior medical director for Celebrex, noted that all NSAIDs carry the same boxed warning about cardiovascular risk, and there was "no way to confirm that one medication is safer than the other for the heart" based on present data.

Some industry watchers question whether a combination pill is necessary given the availability of generic naproxen and over-the-counter PPI's. In an interview, Graham of the FDA said he fears that marketers would try to charge a higher price for a naproxen-Nexium combination pill than that of generic naproxen plus a PPI.

"You can take two tablets for a very low cost," said Graham, who emphasized he wasn't speaking for the FDA. "Unless the proposal to combine the medications together would be at the price of a generic, it's hard to sort of rationalize the increased expense."

AstraZeneca and Pozen say it's too early to talk about pricing for their combination product. According to drugstore.com, a month's supply of Nexium sells for between $136 and $148, depending on the dosage. A month's worth of Celebrex was listed at between $60 and $145, depending on dosage. A month's supply of Prevacid Naprapac costs about $137, according to drugstore.com.

Pozen's Plachetka suggested the combination pill's convenience would be a good selling point.

"People will end up skipping that PPI if they have to take it as a separate pill," Plachetka said. "In our combination product, they can't skip it. I don't think you can put a price on that."

Also, Plachetka thinks a combination naproxen-Nexium would be more effective than a separate-dose regimen in protecting against gastrointestinal side effects. He said Pozen has a proprietary drug-delivery system designed to immediately release the PPI upon ingestion, while delaying release of the naproxen if necessary to protect the stomach.

Pozen and AstraZeneca aren't the only companies trying to develop a new naproxen-based painkiller. NicOx SA (7413.FR) of France is developing naproxcinod, a combination of naproxen and the company's proprietary technology based on nitric oxide. NicOx says the drug has the potential for good gastrointestinal tolerability and safety, with no harmful effects on blood pressure. Data from a late-stage study of the drug are expected to be released soon.

KEY COUNTRY DRUG PURCHASES - RETAIL PHARMACIES

KEY COUNTRY DRUG PURCHASES - RETAIL PHARMACIES
RETAIL DRUG MONITOR: 12 MONTHS TO June 2006
For all the ATC Main Groups
CARDIOVASCULAR, CENTRAL, ALIMENTARY/, RESPIRATORY, ANTI-INFECTIVES, MUSCULO-SKELETAL
GENITO-URINARY, CYTOSTATICS, BLOOD AGENTS, DERMATOLOGICALS, SENSORY ORGANS
DIAGNOSTIC, SYSTEMIC HORMONES, MISCELLANEOUS, HOSPITAL, PARASITOLOGY

Drug Pipeline Series: Approvals --- Oct16-Oct23, 2006

FDA Approves Once-Daily JANUVIA™, the First and Only DPP-4 Inhibitor Available in the United States for Type 2 Diabetes
Merck & Co., Inc. announced that the U.S. Food and Drug Administration (FDA) approved JANUVIA™ (sitagliptin phosphate), the first and only DPP-4 inhibitor available in the United States for the treatment of type 2 diabetes. JANUVIA has been approved as monotherapy and as add-on therapy to either of two other types of oral diabetes medications, metformin or thiazolidinediones (TZDs), to improve blood sugar (glucose) control in patients with type 2 diabetes when diet and exercise is not enough. The recommended dose of JANUVIA is 100 mg once daily. JANUVIA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings.
JANUVIA belongs to a new breakthrough class of prescription medications called dipeptidyl peptidase-4 (DPP-4) inhibitors that improves blood sugar control in patients with type 2 diabetes. JANUVIA enhances a natural body system called the incretin system, which helps to regulate glucose by affecting the beta cells and alpha cells in the pancreas. Through DPP-4 inhibition, JANUVIA works only when blood sugar is elevated to address diminished insulin due to beta-cell dysfunction and uncontrolled production of glucose by the liver due to alpha-cell and beta-cell dysfunction.

FDA Approves New, Once-a-Day COREG CR™ for the Treatment of Three Key Cardiovascular Conditions
GlaxoSmithKline and Flamel Technologies announced FDA approval of once-a-day Coreg CR™ (carvedilol phosphate) extended-release capsules, for the treatment of three cardiovascular conditions:
* High blood pressure, also known as hypertension. * A heart attack that has reduced how well the heart pumps (known medically as post-myocardial infarction left ventricular dysfunction). * Mild to severe heart failure.
COREG CR will utilize Flamel's proprietary Micropump® technology, which controls the delivery of carvedilol helping to maintain appropriate amounts of medicine in the body over a 24-hour span. This technology allows COREG CR to be dosed once daily, in contrast to immediate-release COREG (carvedilol) tablets, which patients must take twice daily. GlaxoSmithKline plans to begin shipping COREG CR in the first quarter of 2007.
COREG CR is a third generation "beta blocker," which is a class of medicines that work by slowing heart rate and lowering the force with which it pumps. Studies of COREG CR indicate it is generally well tolerated with a low incidence of adverse events. COREG CR, a once-a-day medicine, is approved to treat the same conditions as twice-a-day COREG, which has established a significant role in the treatment of heart disease.

FDA Approves Allegra® (fexofenadine hydrochloride) Oral Suspension for Treatment of Seasonal Allergy Symptoms and Chronic Idiopathic Urticaria
Sanofi-aventis U.S. announced that the U.S. Food and Drug Administration (FDA) has approved Allegra® (fexofenadine hydrochloride) Oral Suspension for the twice-daily treatment of symptoms associated with seasonal allergies in pediatric patients, 2 to 11 years of age, and for the treatment of chronic idiopathic urticaria in children 6 months to 11 years of age. This approval makes available a safe and effective seasonal allergy treatment option that is non-impairing to pediatric populations as young as 2 years old.
Seasonal allergic rhinitis is a common chronic condition in children. Symptoms of seasonal allergies include nasal drainage, sneezing, watery eyes and itchy nose, eyes and throat. Studies indicate that seasonal allergy inflammation as well as the impairing side effects of older antihistamines can be disruptive to a child and may affect cognitive skills and function. Allegra Oral Suspension has also been approved for the treatment of chronic idiopathic urticaria (CIU) in twice-daily 30 mg doses for pediatric patients 2 to 11 years of age and twice-daily 15 mg doses for pediatric patients 6 months to 2 years of age. CIU is a rare and bothersome condition characterized by hives lasting more than 6 weeks from an unknown cause. Its symptoms are caused by a reaction to an unknown trigger in the upper layers of the skin.

Schering-Plough Announces FDA Approval of NOXAFIL® (Posaconazole) for Treatment of Oropharyngeal Candidiasis (OPC)
Schering-Plough Corporation reported that the U.S. Food and Drug Administration (FDA) has approved NOXAFIL® (posaconazole) Oral Suspension for the treatment of oropharyngeal candidiasis (OPC), including infections refractory to itraconazole and/or fluconazole. OPC is a fungal infection of the mouth and throat caused by the yeast Candida. NOXAFIL is a novel triazole antifungal agent discovered and developed by Schering-Plough Research Institute.
This approval follows the Sept. 15 FDA approval of NOXAFIL for prophylaxis (prevention) of invasive Aspergillus and Candida infections in patients 13 years of age and older who are at high risk of developing these infections due to being severely immunocompromised, such as hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD) or those with hematologic malignancies with prolonged neutropenia from chemotherapy. Invasive fungal infections are a leading cause of death in these high-risk populations.

FDA Approves REYATAZ® (atazanavir sulfate) 300 mg Single Capsule Formulation in Combination Therapy for Adults With HIV-1 Infection
Bristol-Myers Squibb Company announced that the U.S. Food and Drug Administration (FDA) has granted approval of a new 300 mg single capsule formulation of REYATAZ® (atazanavir sulfate) for the treatment of HIV-1 infection in adults as part of combination therapy. Taken once daily along with ritonavir and food as part of a anti-HIV drug regimen, the REYATAZ 300 mg single capsule formulation can replace two REYATAZ 150 mg capsules for: patients who have previously received anti-HIV medicines, patients who will be receiving tenofovir disoproxil fumarate, and patients who have never taken anti-HIV medicines that require SUSTIVA® (efavirenz) as part of their anti-HIV drug regimen. The REYATAZ single capsule formulation will be available in the United States within seven business days.
REYATAZ is an anti-HIV drug that blocks the action of the HIV protease enzyme, which is needed for the virus to multiply. REYATAZ is a prescription medicine used in combination with other medicines to treat people who are infected with HIV. REYATAZ has been studied in 48-week trials in both patients who have taken or have never taken anti-HIV medicines. REYATAZ does not cure HIV, a serious disease, or help prevent passing of HIV to others. Since REYATAZ was initially approved by the FDA in 2003, approximately 129,000 patients in the United States have been treated with the drug. Bristol-Myers Squibb will continue to produce the currently available REYATAZ 200 mg, 150 mg, and 100 mg once-daily capsules.

Taxotere® Receives U.S. FDA Approval for the Treatment of Patients With Head and Neck Cancer
Sanofi-aventis announced that following a priority review of a supplemental new drug application (sNDA), the U.S. Food and Drug Administration (FDA) has approved Taxotere® (docetaxel) Injection Concentrate in combination with cisplatin and fluorouracil for the induction treatment of patients with inoperable locally advanced squamous cell carcinoma of the head and neck (SCCHN). This approval follows a positive opinion for the same use granted by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMEA) in September of this year.
The FDA based its decision on results from the EORTC 24971/TAX 323 phase III, open-label, randomized study, which enrolled 358 patients with SCCHN.
Patients receiving the Taxotere®-based regimen also had a significantly longer progression-free survival of 11.4 months, compared with 8.3 months (p=0.0077) for the patients receiving a standard therapy. Patients treated with the Taxotere®-based regimen (Taxotere®, cisplatin and fluorouracil) prior to radiation (with or without a surgical component) had a significantly longer median overall survival compared to a standard treatment of cisplatin and fluorouracil (18.6 vs 14.2 months), with a 29 percent risk reduction of death (p=0.0055), a benefit of more than four months improvement in median survival. In the study, induction chemotherapy (also called neoadjuvant therapy) was the first step in treating the disease prior to radiation therapy or surgical intervention.

FDA Approves AstraZeneca's SEROQUEL® For Bipolar Depression Treatment
AstraZeneca announced that the U.S. Food and Drug Administration (FDA) has approved SEROQUEL® (quetiapine fumarate) for the treatment of patients with depressive episodes associated with bipolar disorder. SEROQUEL already is approved for the treatment of acute manic episodes associated with bipolar I disorder** and for the treatment of schizophrenia. SEROQUEL is now the first and only single medication approved by the FDA to treat both depressive and acute manic episodes associated with bipolar disorder.

Drug Pipeline Series: Submissions---Oct16-Oct23, 2006

ROCHE FILES IN EUROPE FOR HERCEPTIN IN ADVANCED BREAST CANCER
Roche has submitted a marketing authorization application to the European Medicines Agency (EMEA) for Herceptin (trastuzumab) as treatment for advanced HER2-positive and hormone-receptor-positive breast cancer. The application is based on data from the international TAnDEM study, which showed that the addition of Herceptin to hormonal therapy doubles the median progression-free survival, from 2. 4 months to 4.8 months.
HER2-positive breast cancer is an aggressive form of the disease that requires special and immediate attention because the tumors are fast-growing and there is a higher likelihood of relapse. Up to a half of HER2-positive breast cancers are also hormone-receptor-positive, a form of the disease that has typically been considered lower risk, due to successful treatment with hormonal therapies. However, TAnDEM is the first randomized study to show that this specific subset of co-positive patients (both HER2- and hormone receptor positive) is actually higher-risk, making the positive results with Herceptin even more meaningful.
TAnDEM is Phase III trial that evaluated Herceptin in combination with the hormonal therapy anastrozole versus anastrozole alone as first-line therapy (or second-line hormonal therapy) in postmenopausal women with advanced (metastatic), HER2-positive and hormone-receptor-positive breast cancer. Enrolment to the trial began in 2001, and 208 HER2 and hormone-receptor co-positive patients were randomized at 77 centers in 22 countries.
Median progression-free survival, the primary endpoint of the trial, was 4.8 months for patients who received the combination compared with 2.4 months for patients who received hormonal therapy alone. Patients in the combination arm also responded significantly better to treatment (overall response rate was 20.3 percent versus 6.8 percent. There was also a positive trend in median overall survival (28.5 months versus 23.9 months), despite the fact that in the hormonal therapy alone arm, more than half of patients crossed over to receive Herceptin during the trial when their disease had progressed, and an additional 15 patients received Herceptin at a later time point.

GW Files Sativex Regulatory Submission In Canada For Cancer Pain
GW Pharmaceuticals plc and Bayer HealthCare, Pharmaceuticals Division - Canada ("Bayer") announce that GW has submitted a regulatory application in Canada for Sativex® to seek approval for a new indication for the treatment of pain in patients with advanced cancer that has not been adequately relieved by opioid medications.
This submission follows a formal pre-submission meeting recently held with Health Canada outlining the evidence of effectiveness of Sativex in this very seriously ill patient population. Following this meeting, Health Canada advised that, on the basis of the clinical data presented, that a submission for consideration under the Notice of Compliance with Conditions (NOC/c) policy could be made. Dr Geoffrey Guy, GW's Chairman, said: "This regulatory submission represents a further step in our broad-based regulatory strategy for Sativex, which is designed to secure approvals for this important new medicine across a range of separate therapeutic indications in countries across the world over the coming years." GW has completed a positive Phase III study in Europe in 177 patients with cancer pain. The trial was a multi-centre double-blind, randomized, placebo-controlled parallel group study. Patients in the study had advanced cancer and were experiencing pain that was not responding adequately to strong opioid medication (e.g. morphine). In addition to study medication, all patients remained on their existing opioid and other analgesic medication during the trial. In this study, Sativex achieved a statistically significant improvement in comparison with placebo in pain as measured on a numerical rating scale (p=0.014), a primary endpoint of the study. A responder analysis showed that 43 per cent of patients on Sativex showed a greater than 30 per cent improvement in their pain (p=0.024). Cancer-related pain can be defined as pain caused by cancer, by cancer treatment such as surgery, radiation therapy or chemotherapy, or by the side effects of treatment. Severe pain is experienced by at least two thirds of patients with advanced disease. It is estimated that between 14 per cent and 47 per cent of these patients will achieve inadequate pain relief from opioid based approaches and will continue to suffer pain.(1)

Drug Pipeline Series: Phase III ---Oct16-Oct23, 2006

AMITIZA™ (lubiprostone) Phase III Constipation Trial Results Demonstrate Improvements in Symptoms of Irritable Bowel Syndrome with Constipation
In recent studies, AMITIZA™ (lubiprostone) demonstrated improvements in relief of symptoms associated with irritable bowel syndrome with constipation (IBS-C), such as abdominal bloating and discomfort. Results of sub-analyses from two Phase III chronic constipation studies of AMITIZA, the first selective chloride channel activator approved by the FDA for the treatment of chronic idiopathic constipation in adults, were presented at the 71st American College of Gastroenterology (ACG) Annual Scientific Meeting.
According to the ACG, as many as 58 million Americans suffer from irritable bowel syndrome (IBS), a condition that accounts for as much as 50 percent of referrals to gastroenterologists each year, and includes IBS-C.
AMITIZA has a novel mechanism of action that works by activating chloride channels to increase fluid secretion in the intestine, thereby increasing the passage of stool and improving signs and symptoms associated with chronic idiopathic constipation. AMITIZA is the only prescription medication for chronic idiopathic constipation that has been approved by the FDA for use in adults, including those 65 years and over and that has demonstrated effectiveness for use beyond 12 weeks.
To evaluate efficacy and symptom improvements in chronic constipation patients treated with AMITIZA with a history of IBS-C, pooled results from two Phase III chronic idiopathic constipation trials were examined. To create an adequate group of IBS-C patients, data from two placebo-controlled clinical trials of 4 weeks were examined together. The pooled IBS-C subgroup consisted of 91 patients: 45 participants received placebo and 46 participants received AMITIZA 24 mcg taken twice daily.

Lilly Launches Phase III 'GALES' Trial of ALIMTA® (Pemetrexed for Injection) in Small Cell Lung Cancer
Eli Lilly and Company has launched a major clinical trial evaluating ALIMTA (pemetrexed for injection) in extensive-stage small cell lung cancer (SCLC), a devastating and rapidly spreading form of lung cancer. This international trial, expected to be the largest ever to be conducted in SCLC(1), will assess the potential clinical benefit of pemetrexed in combination with carboplatin, a commonly-used chemotherapeutic agent, in direct comparison to the current leading treatment option of etoposide in combination with carboplatin.
The trial -- known as GALES for Global Analysis of Pemetrexed in SCLC Extensive Stage -- is a Phase III, global, multicenter, randomized, open-label study that will enroll approximately 1,820 patients with extensive-stage SCLC. The study's primary objective is to compare the overall survival after treatment with pemetrexed plus carboplatin versus etoposide plus carboplatin in previously untreated patients with extensive-stage SCLC. The principal investigator of this study is Nick Thatcher, M.D. of Christie Hospital NHS Trust in Manchester, United Kingdom.
SCLC accounts for between 15 and 20 percent of all lung cancers.(2) Although SCLC is less common than the other main category of lung cancer -- non-small cell lung cancer, SCLC tends to spread more quickly and, as a result, people are typically diagnosed with extensive disease and left without options such as surgery to remove the cancer.

Somaxon Pharmaceuticals' SILENOR™ Demonstrates Positive Results in a Phase 3 Transient Insomnia Clinical Trial
Somaxon Pharmaceuticals, Inc. announced positive results from the company's Phase 3 clinical trial evaluating SILENOR™ (doxepin HCl) in adults with transient insomnia. SILENOR™ demonstrated statistically significant improvements compared to placebo (p<0.0001) in the primary endpoint of this trial, Latency to Persistent Sleep (LPS), a measure of sleep onset. SILENOR™ also produced statistically significant improvements relative to placebo in multiple secondary endpoints, including measures of both sleep onset and sleep maintenance.
This Phase 3 trial was a randomized, double-blind, placebo-controlled, multi-center, parallel group study that enrolled 565 adults in a sleep laboratory setting using a phase-advance, first night assessment model of induced transient insomnia. Efficacy assessments evaluated both objective PSG (polysomnography) and subjective measures of sleep. Results demonstrated that 6mg of SILENOR™ was effective at inducing sleep and maintaining sleep throughout the night.
SILENOR™ achieved statistically significant results in multiple endpoints including:
* Latency to Persistent Sleep (LPS): Improvement compared with placebo of 13 minutes (p<0.0001) * Latency to Sleep Onset (LSO), a subjective measure: Improvement compared with placebo of 16 minutes (p<0.0001) * Wake After Sleep Onset (WASO): Improvement compared with placebo of 40 minutes (p<0.0001) * Total Sleep Time (TST): Improvement compared with placebo of 51 minutes (p<0.0001)

NEUROGESX REPORTS RESULTS OF POST-HERPETIC NEURALGIA STUDY
NeurogesX has announced positive results from a multicenter, double-blind, controlled Phase III trial of Transacin (NGX-4010), the company's high-concentration trans-capsaicin dermal patch, in patients with post-herpetic neuralgia (PHN). The study met its prespecified primary endpoint with patients reporting statistically significant pain reduction after a single one-hour application of Transacin. A significant reduction in pain was noted during the first week following treatment and was maintained throughout the 12-week study period. At 12 weeks, more than one-half of all subjects treated with Transacin reported improvement in their condition, as measured by the Patient Global Impression of Change scale.
The study was conducted at 53 clinical sites in the U.S. A total of 402 patients suffering from PHN were randomized to a single, one-hour treatment with Transacin or to a matching, low-concentration capsaicin control patch. Study subjects were then followed for 12 weeks. Pain was recorded daily by study subjects using the Numeric Pain Rating Scale of zero (no pain) to 10 (worst possible pain).
Transacin is a topical, physician-administered patch containing a high concentration of trans-capsaicin, a synthetic form of the naturally occurring TRPV1 agonist capsaicin. Unlike current treatment approaches for neuropathic pain that include opioids and other agents - which act on the central nervous system and can cause drowsiness or other systemic side effects - the patch is designed to act peripherally in the skin, where the pain frequently originates. The incidence for safety issues or side effects that negatively impact quality of life is expected to be low.

Drug PipelineSeries: Phase II --- Oct16-Oct23 2006

Osiris Therapeutics Reports Positive Phase II Results Using PROCHYMAL™ in Treatment-Resistant Crohn's Disease
Osiris Therapeutics announced positive results from a pilot phase II study using PROCHYMAL for the treatment of patients with moderate to severe Crohn's disease who had failed to respond to standard treatments such as steroids and infliximab (Remicade®). In the study, every patient evaluated reported a reduction in Crohn's Disease Activity Index or CDAI after receiving two infusions of PROCHYMAL. There was a statistically significant decrease in mean CDAI scores of 105 points by day 28 from 341 to 236 (p=0.004). The results will be presented by Dr. Jane Onken, Director of the Inflammatory Bowel Disease Clinic and Associate Professor of Medicine at the Duke University School of Medicine at the Annual Meeting of the American College of Gastroenterology on October 24. Dr. Onken was the lead investigator for the trial.

ChemoCentryx Reports Promising Clinical Activity for Traficet-EN® From Phase 2 Trial for the Treatment of Crohn's Disease
ChemoCentryx, Inc., a clinical-stage, biopharmaceutical company developing orally-administered therapeutics that target the chemokine and chemoattractant systems, announced positive data from the company's Phase 2 clinical trial of Traficet-EN® (CCX282-B) for the treatment of Crohn's disease at the 14th United European Gastroenterology Week (UEGW 2006) meeting in Berlin, Germany. Traficet-EN® is a first-in-class, orally active, anti-inflammatory agent that targets the chemokine receptor known as CCR9.
The four-week Phase 2 clinical trial enrolled 74 patients with moderate-to-severe Crohn's disease to primarily assess Traficet-EN's safety and tolerability. Patients were randomized on a 2:1 basis to receive 250 mg of Traficet-EN once daily for 28 days or placebo. Traficet-EN was very well tolerated: incidence of adverse events was approximately similar to those observed in the placebo group. Clear signs of clinical activity, measured by a drop in blood levels of C-reactive protein (CRP) were observed in the patients receiving Traficet-EN compared to placebo.

ZymoGenetics Begins Phase 1/2 Clinical Trial With IL-21 and Nexavar in Patients With Renal Cell Cancer
ZymoGenetics, Inc. announced the start of a Phase 1/2 clinical study of Interleukin 21 (IL-21) in combination with Nexavar® (sorafenib) in patients with advanced renal cell cancer. The study will evaluate the safety and preliminary anti-tumor activity of IL-21 in combination with Nexavar.
The open-label, dose-escalation multi-center U.S. trial is expected to enroll 48 patients with metastatic stage IV renal cell cancer. The Phase 1 part of the study will establish the maximum tolerated dose of IL-21 given for one treatment course, consisting of two 5-day cycles of IL-21 in combination with a standard dose of Nexavar administered over a 6-week period. The Phase 2 part of the study will further evaluate the safety and preliminary anti-tumor activity of IL-21 at the dose established in Phase 1 in combination with Nexavar.

YM BioSciences announces results of AeroLEF™ Phase IIb open-label study
YM BioSciences Inc. announced results from the open-label portion of its Phase IIb trial (DLXLEF-AP4) of AeroLEF™.
The results demonstrated that the majority of the patients were able to achieve effective analgesia for episodes of moderate to severe acute post-surgical pain by self-titrating the amount of medication they inhaled using AeroLEF™. Results of the study were presented at the American Society of Anesthesiologists (ASA) Annual Meeting in Chicago, IL.
AeroLEF is a unique, inhaled-delivery composition of free and liposome-encapsulated fentanyl, in development for the treatment of moderate to severe pain, including cancer pain. AeroLEF is designed to permit patients to match dosage to their individual pain intensity and experience rapid and extended pain relief.
In the study, patient self-titrated dosing with AeroLEF provided clinically meaningful analgesia in 81 percent, 100 percent and 87.5 percent of treated pain episodes during doses 1, 2 and 3 respectively. Within 10 minutes of initiating dosing with AeroLEF, 38 percent, 73 percent and 63 percent of patients reported a reduction in pain intensity to mild pain during doses 1, 2 and 3 respectively. Achieving effective pain relief was the reason for stopping AeroLEF dosing in 35 of 40 (88 percent) treated pain episodes.

AVANIR Announces Publication of Phase II Diabetic Neuropathic Pain Trial Results
AVANIR Pharmaceuticals announced that results of a Phase II clinical trial evaluating escalating doses of Neurodex™ in the treatment of painful diabetic neuropathy were published for the first time in the October issue of Clinical Therapeutics (Vol 28, Number 10, 2006).
The open label trial, conducted at five U.S. sites in 36 patients with painful diabetic neuropathy, assessed the safety and tolerability of Neurodex, a proprietary formulation of dextromethorphan (DM) and low dose quinidine (Q). A preliminary assessment of the drug candidate's efficacy in the treatment of painful diabetic neuropathy was obtained using pain ratings scales and patient diaries. At the end of the study, mean changes from baseline using Pain Intensity Rating Scale and the Pain Relief Rating Scale scores were highly statistically significant (p less than 0.001). Daily patient diary assessments also demonstrated statistically significant improvements in sleep, present pain intensity, activity and pain rating scales (p less than 0.001 in each case).
Adverse events related to Neurodex were mild to moderate and were consistent with the previously known effects of the drug. Adverse events reported included nausea, dizziness and headache. Three patients did not complete the study, two due to adverse events and one due to inability to comply with the protocol. Ninety-two percent of participants completed the study, and 70% of the subjects that completed the study tolerated the maximum allowed dose (60DM/60Q dosed twice per day).

Medivation Begins Phase 1-2a Trial of Dimebon™ in Huntington's Disease
Medivation, Inc. announced that patient dosing has begun for its Phase 1-2a clinical trial of Dimebon™ to treat Huntington's disease.
Medivation is conducting the Huntington's disease trial in collaboration with the Huntington Study Group (HSG), a network of more than 250 experienced clinical trial investigators, coordinators and consultants from more than 60 academic and research institutions throughout the United States, Canada, Europe and Australia. The study will be conducted at approximately 12 HSG sites in the United States and led by principal investigator Karl Kieburtz, M.D., M.P.H., professor of neurology at the University of Rochester and director of the HSG Clinical Trials Coordination Center.
The Huntington's disease clinical trial has two parts: a dose-escalation phase to determine the optimal doses of Dimebon, followed by a three-month randomized, placebo-controlled, double-blinded phase to evaluate the safety and preliminary efficacy of those doses in approximately 75 Huntington's disease patients. The second part of the study will begin after additional animal toxicology studies, requested by FDA and now underway, have been completed. The primary efficacy endpoint in the trial is the Unified Huntington's Disease Rating Scale (UHDRS), and results are expected in the second half of 2007.

Forest Labs, Replidyne Down On FDA Rejection Of Drug

The Food and Drug Administration rejected an application for marketing approval for a new antibiotic, sending shares of the drug's developer, Replidyne Inc. (RDYN), plunging about 50% Monday, while Replidyne marketing partner Forest Laboratories Inc. (FRX) was off almost 6%.

The companies indicated it could take at least two years to complete additional studies of the drug to address FDA concerns.

Replidyne shares fell $5.19 to $5.05 on volume of 2.8 million, above the daily average of 50,455. Forest Labs shares were off $3.06 at $48.41 on volume of 2.6 million, above the daily average of 2.2 million.

Replidyne, Louisville, Colo., applied in December for FDA approval of faropenem medoxomil, which is designed to combat forms of sinusitis, pneumonia and other infections. Replidyne signed a licensing agreement in February giving New York-based Forest Labs primary responsibility for sales and marketing of the drug.

The FDA issued a non-approvable letter for faropenem medoxomil and recommended further clinical studies for all the uses for which Replidyne sought approval, the companies said in a press release Monday. In particular, FDA may require "superiority studies" for the antibiotic's use to treat acute bacterial sinusitis and acute exacerbation of chronic bronchitis. Also, the FDA may require additional microbiologic evaluation for the drug's use to treat community-acquired pneumonia, the companies said.

The FDA didn't raise any safety concerns or issues surrounding the chemistry, manufacturing or controls for the product, the companies said.

Replidyne and Forest Labs plan to discuss the clinical plans for the drug with the FDA, including the number of trials needed for each use. The companies expect a minimum of two years will be required to complete the studies.

"We are disappointed that the FDA is requiring additional clinical trials," Replidyne Chief Executive Kenneth Collins said in a press release. "However, we believe that at the doses studied faropenem has a clearly demonstrated favorable safety profile. Replidyne is in a strong financial position to continue the development of faropenem with our partner Forest and to advance our promising pipeline."

Replidyne and Forest also plan to discuss their licensing agreement based on the FDA decision, the companies said in the press release.

Personal Health Report: A Safer Prescription For Menopause?

Scared away from hormones, millions of women are turning to other drugs to cope with hot flashes and other symptoms. But they may be taking on a whole new set of risks.

After a major government study four years ago raised questions about the safety of hormone drugs, many women stopped taking the pills.

But that doesn't mean they stopped taking drugs.

Today, women are using a litany of drug regimens to cope with many symptoms of menopause that in the past were treated by hormones alone. Antidepressants are prescribed to calm hot flashes and mood changes. Bone drugs are offered to prevent osteoporosis. Sleep aids help with the restless nights that often afflict middle-aged women. Prescription anti-inflammatory pills help ease the aches and pains common in menopause.

Now, with the menopausal medicine cabinet overflowing with more drugs than ever before, many doctors and women's health advocates are starting to worry. At a time when we finally know more than ever about the full range of risks and benefits of hormone drugs, women instead are gobbling down a different set of pills backed by very little science and long-term safety data. After years of fighting for more research into the real risks and benefits of menopause hormones, many doctors, researchers and women's groups now wonder whether women are really any better off. Has the shift away from hormones made women safer, or has it just subjected them to a whole new set of drug risks?

"It's horrible what they're trying to give to women now," says Barbara Seaman, who in 1975 helped found the National Women's Health Network, a group that has battled for more research on women's health issues, including the risks and benefits of menopause hormones. Ms. Seaman remembers sitting at a government health conference last year and listening to doctors describe the various drugs used now to treat menopause. She says the shift from hormones to other drug treatments reminded her of an old folk song where a young man traded his first wife for an abusive second wife.

"That's how I feel now," says Ms. Seaman. "Give me my old wife back."

The new prescription for menopause was spurred by the Women's Health Initiative, a study of more than 27,000 women who used menopause hormones or a placebo. In July 2002, the first part of the hormone study was stopped because women using estrogen and progestin appeared to be at higher risk for heart attacks and breast cancer. In the years since the WHI results were first announced, a closer look at the study data shows that it was primarily older women who started taking the hormones long past menopause who had health problems from hormones. Younger women who began taking the drugs at the time of menopause appeared to have far fewer risks, and in some cases hormones appeared to protect women from heart problems and other health worries, though the data aren't conclusive.

But that hasn't stopped women from abandoning hormones in droves. Sales of menopause hormones dropped 33% from 2001 to an estimated $1.9 billion last year. And the decline hasn't stopped. Sales of estrogen and progestin combination drugs dropped 8% in the first six months of this year from the year-earlier period, and estrogen sales fell 4%, according to IMS Health, a pharmaceutical information and consulting company in Plymouth Meeting, Pa.

One of the biggest shifts in menopause treatment in recent years has been the prescribing of antidepressant drugs to treat hot flashes. The drugs aren't approved by the Food and Drug Administration as a hot-flash remedy, but doctors now prescribe them "off label" for the purpose.

Popular antidepressants act by increasing levels of a brain chemical called serotonin. While the drugs are effective against depression, nobody really knows how or why altering a woman's brain chemistry might work to stem hot flashes. It may be that adjusting a woman's serotonin levels affects the part of her brain that controls body temperature. Another theory is that serotonin influences levels of a woman's natural estrogen. Hot flashes are triggered by fluctuating levels of estrogen.

Studies show that antidepressants do appear to curb hot flashes, but not as well as estrogen. And while the benefits of antidepressants in treating hot flashes appear to be small, some of the side effects may make women feel worse. In May, the Journal of the American Medical Association reported that there have been only six small studies of serotonin-altering antidepressants for the treatment of hot flashes. However, only two of them -- trials of Wyeth's Effexor and GlaxoSmithKline PLC's Paxil -- met scientific standards for "good quality" studies, the JAMA review said. That means most of what we know about antidepressants and hot flashes comes from just 386 women who took the drugs for six weeks or less.

The studies looked at whether antidepressants could reduce the number of hot flashes a woman has each day. A woman with moderate to severe menopause symptoms has at least seven or eight hot flashes a day, and about one-third of women who suffer from hot flashes have more than 10 a day. But in the Paxil trial, the antidepressants eliminated only about one more hot flash a day than women on placebo. By comparison, estrogen reduces the frequency of hot flashes by 77%, or about 2.5 to three hot flashes daily compared with placebo, according to the JAMA report.

The Effexor trial looked at three different doses of the drug. At the lowest dose, the drug reduced hot flashes by only 37%, compared with 27% for placebo. When the dose jumped to 75 milligrams and 150 mg, the drug group reported about 60% fewer hot flashes. But there was a downside. The women who were taking the two largest doses also experienced the most side effects, including loss of appetite, dry mouth, nausea and constipation.

Antidepressants' side effects worry many doctors, in part because menopausal women may be particularly vulnerable to some of them. One area of concern is possible sexual problems, including loss of libido -- problems to which women may be susceptible anyway during the hormonal chaos of menopause.

Rutgers University anthropologist Helen Fisher has conducted brain-scan studies that suggest antidepressants also blunt important emotions related to love, romance and long-term attachment. They may do this by interfering with dopamine, a brain chemical connected with emotion and feelings of pleasure. An April 2005 mouse study in the medical journal Neuron showed that antidepressants not only affect serotonin levels in the brain, but also "hijack" dopamine signaling as well. That means brain transmitters that are supposed to carry dopamine around the brain appear to end up carrying serotonin.

The fact that antidepressants blunt emotions and interfere with sex is particularly concerning for menopausal women, who may be especially vulnerable to relationship problems as a result of the physiological changes of menopause as well as other midlife issues, like kids leaving for college or a husband's approaching retirement.

"You are taking a chance of jeopardizing your ability to fall in love and stay in love and feel attachment to the people around you when you take antidepressants," Dr. Fisher says. "And with menopause we usually aren't talking about giving these drugs to women who are depressed. We are talking about normal women who enjoy caring about their families, enjoy caring about their work, home and future plans. So you're taking a normal brain and blunting all these precious emotions that are the joy of living. Do you really want to give all that up to treat hot flashes?"

Beyond the known side effects from antidepressants, nobody understands the long-term impact of using them in women with normal brain chemistry who aren't depressed. It is known that taking antidepressants results in certain changes in brain receptors. That's why people who try to stop the medications can sometimes develop severe withdrawal symptoms until the brain receptors return to normal. Doctors believe antidepressants are potentially life-saving drugs for people coping with moderate to severe depression, so the risks and side effects likely are worth it. But they question the use of antidepressants in menopausal women who don't suffer from depression.

"People should not be taking these drugs for nonpsychiatric indications unless there are studies to back up their effectiveness and safety," says Grant Mitchell, chief of psychiatry at Northern Westchester Hospital in Mount Kisco, N.Y. "If these were harmless drugs with no side effects, we might look at it differently. But they're not -- they are mind-altering medications."

A spokesman for GlaxoSmithKline, maker of Paxil, says that the company isn't seeking FDA approval to use the drug as a hot-flash treatment and that the decision on whether to use Paxil for that purpose is one made between doctors and patients. The company emphasizes that Paxil has a long track record for safety. "Paxil's been used safely and effectively in millions of patients since it was first approved," the spokesman said.

In July, Wyeth, maker of Effexor, filed for FDA approval of another type of serotonin drug called Pristiq, to be used in the treatment of hot flashes. The company says in its early studies, the incidence of decreased libido wasn't any different with Pristiq than with placebo. The Pristiq studies also are based on healthy women who aren't depressed.

Another concern among many doctors is that a depressed person using antidepressants should be monitored closely because of a potentially higher risk for suicide in the early months of antidepressant use. Psychiatrists worry that if a gynecologist or family doctor puts a woman with undiagnosed depression on the drugs to treat hot flashes, she won't get the follow-up attention she needs.

An unanswered question is whether giving antidepressants to a healthy brain could trigger mental-health problems later on. A Wyeth spokeswoman, says there's no evidence of harmful brain changes from any of the serotonin drugs, which have been safely used for decades in millions of patients. However, doctors say more research is needed. For instance, a small percentage of patients, such as those with a family history of bipolar disorder or manic personality traits, may be at risk of developing severe manic symptoms after starting antidepressants.

"Before you cavalierly place women on antidepressants for hot flashes, you have to give them a full psychiatric evaluation," says Shari Lusskin, director of reproductive psychiatry at the New York University Medical Center. "Does exposure to an antidepressant in a nondepressed patient lead to significant changes in brain chemistry that could have a negative effect or does it increase vulnerability to a mood disorder? I'd say we don't know."

Another major shift in recent years has been in the treatment of osteoporosis. The Women's Health Initiative found that menopause hormones boost bone density and dramatically reduce a woman's risk for fracture. But because of the other health worries, many women have switched to bone drugs called bisphosphonates, which are sold under various brand names including Merck & Co.'s Fosamax.

Bones are in a constant state of remodeling -- dissolving microscopic bits of old bone, a process called resorption, and rebuilding new bone. After about the age of 30, a woman's bones start to dissolve faster than they can be rebuilt, which is why some women eventually develop thin, brittle bones that are easily broken. The pace of bone loss increases dramatically after menopause.

The bisphosphonates work by slowing the bone remodeling process. Studies show that bisphosphonates do increase a woman's bone density and lower her risk for bone fractures. But what's not clear are the long-term effects of using a drug that interrupts a key phase of the bone remodeling and renewal cycle.

Even though short-term suppression of the dissolving process seems to strengthen bone, questions remain about whether long-term use of bisphosphonates has the potential to weaken bones. The worry is that every day, tiny microscopic cracks form in bone as a result of normal wear and tear. But with part of the bone remodeling process suppressed, those cracks may not be repaired. Over time, the worry is that many more cracks could accumulate, leading to a long-term weakening of the bone. A 2001 study in the medical journal Bone studied the effect of high doses of bisphosphonates on the bones of beagles and found an accumulation of microdamage. However, researchers haven't yet identified the same pattern in human subjects. Merck notes that the beagle studies showed that the beagle bones weren't any weaker as a result of the microcrack accumulation.

Susan M. Ott, associate professor of medicine at the University of Washington in Seattle, says the bone drugs are an important treatment for older women suffering from severe osteoporosis. Her concern is that many women in their 40s and 50s -- who in the past would have been prescribed estrogen -- are now being given bisphosphonates to prevent osteoporosis.

"It makes me feel a little uneasy," says Dr. Ott, who last year wrote an editorial in the Journal of Clinical Endocrinology & Metabolism raising concerns about the long-term risks of the drugs. "We have 45- and 50-year-old women who don't really have anything wrong who are on these bisphosphonates that they are presumably going to take until they are 70? It's kind of scary because we don't know what happens if you take them that long."

But other doctors say the evidence so far suggests the drugs are safe. Ethyl Siris, director of the osteoporosis center at Columbia University Medical Center in New York, notes that the drugs don't suppress bone resorption entirely -- they simply slow the rate down to that of a young adult woman. "There have been no alarm signals suggesting long-term safety issues in bone," says Dr. Siris, who says she has consulted with companies that sell bone drugs.

Arthur Santora, executive director of clinical research and endocrinology for Merck, says the company has 10 years of clinical-trial data looking at bone density and turnover, and there's no evidence that the drug's effect on bone turnover changes over time. "I think we can be pretty sure that there are no apparent problems in safety and no theoretical concerns about decreasing turnover," says Dr. Santoro. "There is nothing that would predict a problem beyond 10 years."

The known side effects of bisphosphonates can include esophageal problems, heartburn and ulcers. In rare cases a flulike illness might result. Another rare problem is osteonecrosis of the jaw, a disease in which a patient's jawbone rots and dies.

Merck notes that in 10 years of study of more than 17,000 patients, there haven't been reports of osteonecrosis of the jaw in its own clinical trials. The majority of patients suffering from the jaw complication are cancer patients taking a potent intravenous form of the drug to stop cancer cells from dissolving bone. However, a small number of other cases from noncancer patients using oral bisphosphonates also have been reported. Doctors say these patients typically have used the drugs for seven or eight years. It's simply not clear who is at risk of this complication, but some doctors suggest that patients taking drugs like Fosamax avoid major dental or oral surgery if they can. Such surgery may be the trigger for problems, because the jaw bones are slower to heal and complications develop.

Menopausal women are also candidates for a number of other drugs as alternatives to estrogen. Sleep drugs, such as Sanofi Aventis's Ambien and Sepracor Inc.'s Lunesta, are options for women suffering from sleep disturbances related to menopause. While the drugs are considered safe, the concern is that the sleep problems associated with menopause can last for years. "The question is, how long do you treat them for?" says Dr. Lusskin from NYU. "We don't want everybody addicted to sleeping pills. People become dependent on these drugs."

Some menopausal women who have stopped taking hormones also have noticed an increase in body aches, stiffness and pain. A Swedish study of nearly 4,000 women estimated the incidence of body pain to be between 50% and 70% among menopausal women, depending on their age. It's a little-known fact that estrogen appears to provide relief to body pain. In the WHI, treatment with estrogen and progestin resulted in a 25% improvement in general aches and pains and a 43% reduction in joint pain and stiffness.

But now women with aches are more likely to be given prescription anti-inflammatory drugs such as Celebrex, or over-the-counter drugs like ibuprofen or naproxen, the pain reliever in Aleve. The FDA has added strong warning labels to these and other painkillers, after some studies linked pain drugs with an increased risk for heart attack, stroke and other cardiovascular problems. The concerns prompted the withdrawal of Merck's pain drug Vioxx from the market.

Dr. Lusskin notes that her main concern about the wide range of drugs being used during menopause is that many women have the impression that they are safer than taking hormones. "People are saying, 'If it's hormones we won't take it, but I'll take anything else you'll hand me,'" says Dr. Lusskin. "But there's no medical treatment that has only benefits and no risks. Patients have to be educated consumers and think carefully about what drugs they're going to take."