investigators

Novartis restructures its development strategy

Tue, 20 May 2008 06:59:56 -0400

Novartis CEO Daniel Vasella (photo) tells the Wall Street Journal that he knew Novartis had become too big and too bureaucratic when one of the company's top scientists expressed delight at finally meeting him. So he's set out to reconstruct the drug giant he built, with a particular emphasis on drug discovery.

At the top of the pipeline: two meningitis vaccines that could become blockbusters. And the new pharma chief--Joe Jimenez--is breaking up investigators into small teams so they can go one on one with regulators to see if they should move ahead with a development program.

- read the article from the Wall Street Journal

Developers seek alternatives to animal ingredients

Tue, 01 Apr 2008 07:59:57 -0400

The brouhaha over heparin has cast a spotlight on the use of animal products in therapies. It also underscores new development activities aimed at coming up with synthetic versions of drugs that will circumvent the need to source materials from animals. Altus Pharmaceuticals, for example, is developing an alternative to heparin with the help of financing from the Cystic Fibrosis Foundation.

When tainted heparin was first linked to the deaths of patients, investigators quickly focused on the role that an active ingredient extracted from pig intestines may have played. Most of those ingredients are now sourced in China and would be threatened by any serious viral outbreak in those animals.

- read the article in the New York Times

Related Articles:
Post-heparin, no oversight excuses. Report
Heparin recall spreads in Europe. Report
More heparin recalled. Report
Baxter: Fake heparin predated API. Report

FDA getting tougher with refuse-to-file letters

Tue, 26 Feb 2008 06:59:57 -0500

More bad news on the big drought of new drug approvals. Not only are approvals at a 25-year low while non-approvable letters and black box warnings are on the rise. Now the RPM Report says that "refuse-to-file" letters are also spiking. Last year there were eleven refuse-to-files, compared to three in 2004 and four in 2005. Last year there were seven. And the 11 refusals, where the agency rejects an application for review, are particularly disturbing when you compare it to the 19 NCE approvals last year. FDA officials say the drug developers should have seen it coming.

"There's a factor in there of inexperience and lack of regulatory savvy, but also maybe they get too invested or too wedded to their product and can't see the forest by being buried in the application," New Drugs Director John Jenkins tells RPM. "We do see cases where it's so clear to us that this isn't going to get approved."

- read the story in the RPM Report

ALSO: The RPM Report is predicting--or perhaps just speculating--that the FDA is gearing up for a significant crackdown on drug investigators. Report

Related Articles:
2007 FDA approvals. Report
Dry spell or parched desert for NME approvals? Report
New drug approval lags in 2007. Report
FDA quick to reject drugs as it gets more cautious. Report

Novo Nordisk reports positive data in diabetes trials

Mon, 20 Aug 2007 06:59:58 -0400

Denmark's Novo Nordisk has seen its shares surge on the news that Liraglutide has produced positive results in two late-stage trials, positioning it for regulatory approval next year. The two Phase III trials are the second and third legs among five late-stage studies of the drug. And in these two steps the drug reduced weight and improved glucose control. Roughly 40 percent of patients hit the American Diabetes Association's goal of average blood glucose control (HbA1c) of 7 percent.

"The encouraging clinical results from the two new trials confirm the positive effect of Liraglutide...and leave us confident that we are on track to submit for regulatory approval mid-2008," said Novo Nordisk chief science officer Mads Krogsgaard Thomsen.

- check out the release
- read the report from the PharmaTimes

Related Articles:
Investigators probing Novo payments. Report

UK lab denies involvement in deadly outbreak

Wed, 08 Aug 2007 06:59:56 -0400

A UK lab jointly owned by Merck and Sanofi-Aventis insists that there is no evidence that it played any role in a recent outbreak of foot-and-mouth disease, despite an initial report from a regulatory group that they were the likely culprits in the case. Merial Animal Health says that its own investigation has given it "complete confidence" in its compliance on safety issues. Investigators, though, say that the strain of foot-and-mouth disease found in nearby cattle is the same strain that the lab has been working on. And government officials say that they will have to investigate whether the outbreak was a deliberate act of sabotage. A farmers' group says they may sue.

- see Merial's response to the accusations
- here's the article from The Guardian

Press Release: Scientists Discover Key to Manipulating Fat

Maureen Martino — Tue, 03 Jul 2007 10:09:59 -0400

Scientists Discover Key to Manipulating Fat

Pathway also explains stress-induced weight gain

Washington, D.C.--In what they call a “stunning research advance,” investigators at Georgetown University Medical Center have been able to use simple, non-toxic chemical injections to add and remove fat in targeted areas on the bodies of laboratory animals. They say the discovery, published online in Nature Medicine on July 1, could revolutionize human cosmetic and reconstructive plastic surgery and treatment of diseases associated with human obesity.

Investigators say these findings may also, over the long-term, lead to better control of metabolic syndrome, which is a collection of risk factors that increase a patient’s chances of developing heart disease, stroke, and diabetes. Sixty million Americans were estimated to be affected by metabolic syndrome in 2000, according to a study funded by the Centers for Disease Control in 2004.

In the paper, the Georgetown researchers describe a mechanism they found by which stress activates weight gain in mice, and they say this pathway ? which they were able to manipulate ? may explain why people who are chronically stressed gain more weight than they should based on the calories they consume.

This pathway involves two players ? a neurotransmitter (neuropeptide Y, or NPY) and the receptor (neuropeptide Y2 receptor, or Y2R) it activates in two types of cells in the fat tissue: endothelial cells lining blood vessels and fat cells themselves. In order to add fat selectively to the mice they tested, researchers injected NPY into a specific area. The researchers found that both NPY and Y2R are activated during stress, leading to apple-shape obesity and metabolic syndrome. Both the weight gain and metabolic syndrome, however, were prevented by administration of Y2R blocker into the abdominal fat.

“We couldn’t believe such fat remodeling was possible, but the numerous different experiments conducted over four years demonstrated that it is, at least in mice,” said the study’s senior author, Zofia Zukowska, M.D., Ph.D., professor and chair of the Department of Physiology & Biophysics at Georgetown University Medical Center.

“We are hopeful that these findings might eventually lead to control of metabolic syndrome, which is a huge health issue for many Americans,” she said. “Decreasing fat in the abdomen of the mice we studied reduced the fat in their liver and skeletal muscles, and also helped to control insulin resistance, glucose intolerance, blood pressure and inflammation. Blocking Y2R might work the same way in humans, but much study will be needed to prove that.”

More immediately, the findings could provide some comfort to stressed individuals who blame themselves for a weight gain that seems outsized given the food they eat, said Lydia Kuo, a medical student who earned her Ph.D. in physiology due to work on the study.

“This is the first study to show that stress has a direct effect on fat accumulation, body weight and metabolism,” she said. “In humans, this kind of stress-mediated fat gain may have nothing to do with the brain, and is actually just a physiological response of their fat tissue.”

And perhaps the most rapid clinical application of these results will be in both cosmetic and reconstructive plastic surgery, said co-author Stephen Baker, M.D., D.D.S, associate professor of plastic surgery at Georgetown University Hospital. The ability to add fat as a graft would be useful for facial rejuvenation, breast surgery, buttock and lip enhancement, and facial reconstruction, he said, and using injections like those tested in this study could make fat grafts predictable, inexpensive, biocompatible and permanent.

Equally important, blocking Y2R resulted in local elimination of adipose, or fat, tissue, said Baker. “This is the first well-described mechanism found that can effectively eliminate fat without using surgery,” he said. “A safe, effective, non-surgical means to eliminate undesirable body fat would be of great benefit to our patients.”

Roxanne Guy, MD, president of the American Society of Plastic Surgeons, of which Baker is a member, is also excited by the findings, although she agrees that more research is needed to find out how the animal findings translate in humans. “Providing a long lasting, natural wrinkle filler and a scientifically studied, non-surgical method for melting fat could revolutionize ‘growing old gracefully,’” she said. “This discovery could also have positive implications for reconstructive plastic surgery procedures performed on the face and breasts.”

Stress + “comfort” foods = excess weight gain

As part of the study, Zukowska and her team examined the effect of several forms of chronic stress that mice in the wilderness can encounter, such as exposure for an hour a day over a two-week period to standing in a puddle of cold water or to an aggressive alpha mouse, and they conducted the experiments in combination with a regular diet or with a high-fat, high-sugar diet. Stressed animals fed a normal diet did not gain weight, but stressed mice given a high-fat diet did. In fact, the researchers found these mice put on more weight than expected given the calories they were consuming.

“They gained twice as much fat as would be expected, and it was all in their belly area,” Kuo said. Stressed versus non-stressed animals ate the same amount of food, but the stressed animals processed it differently, she said, explaining, “the novel finding here is that NPY works on fat tissue, not in the brain.” This finding makes sense if evolutionary advantage is considered, Zukowska said. “If you can store fat for times of hardship, you have a fat reserve that can be turned into energy for the next fight.

“The same mechanism may be happening in humans,” she said. “An accumulation of chronic stressors, like disagreements with your boss, taking care of a chronically ill child, or repeated traffic road rages, could be acting as an amplifier to a hypercaloric diet when protracted over time. Depression may also be acting as a stressor.” Not only were the stressed mice much fatter, they began to exhibit the metabolic and cardiovascular consequences of obesity, Kuo said. “They had the glucose intolerance seen in diabetes, elevated blood pressure, inflammation in the blood vessels, and fat in their livers and muscles.”

“Although we don’t expect that, in the future, a person will be able to eat everything he or she wants, chase it down with a Y2R blocking agent, and end up looking like a movie star,” said Zukowska, “we are encouraged that these findings could improve human health.”

“The concepts described in this study might give us the tools to design one method to remodel fat and another to tackle obesity and metabolic syndrome,” Baker said. “It is very exciting.”

The study was funded by National Institutes of Health grants awarded to Zofia Zukowska, a Predoctoral Mid-Atlantic Fellowship to Lydia Kuo from the American Heart Association, a contract from the Slovak Research and Development Agency to co-author Richard Kvetnansky, and grants from National Institutes of Health and the Plastic Surgery Educational Foundation awarded to a co-author Stephen B. Baker. Co-authors include Lydia E. Kuo, Ph.D., Joanna B. Kitlinska, Ph.D., Jason U. Tilan, M.S., Lijun Li, M.D., Stephen B. Baker, M.D., DDS, Michael D. Johnson, Ph.D., all from Georgetown University, Edward W. Lee, M.D., PhD, from the University of California-Los Angeles, Mary Susan Burnett, Ph.D., from Washington Hospital Center, Stanley T. Fricke, Ph.D., from Georgetown University, Richard Kvetnansky Ph.D., from Slovak Academy of Sciences, Bratislava, Slovakia, Herbert Herzog, Ph.D. from Garvan Insitute, Sydney, Australia, and Zofia Zukowska, M.D., Ph.D. from Georgetown University.

About Georgetown University Medical Center
Georgetown University Medical Center is an internationally recognized academic medical center with a three-part mission of research, teaching and patient care (through our partnership with MedStar Health). Our mission is carried out with a strong emphasis on public service and a dedication to the Catholic, Jesuit principle of cura personalis -- or "care of the whole person." The Medical Center includes the School of Medicine and the School of Nursing and Health Studies, both nationally ranked, the world-renowned Lombardi Comprehensive Cancer Center and the Biomedical Graduate Research Organization (BGRO).

Editor's Corner

Sun, 28 Jan 2007 19:01:39 -0500

It's far too early to tell just how damaging the new report about GlaxoSmithKline (below) will be to the industry. The BBC is reporting that the company distorted data in an attempt to gain an approval for Seroxat to treat depression in children. Whether or not the report holds up under scrutiny, the news once again raises questions about the way trial data is reported, the independence of the investigators involved and the ability to mask potentially harmful outcomes. The industry has yet to agree to an effective way to ensure that all relevant trial data is made public and that it maintains an arm's length relationship with researchers. But it's clear that the time for that is long past due. A more honest approach is essential to regaining the public's trust, which will only come with independent verification. Yes, some therapies may be held up to additional scrutiny and may lose access to some markets. But that's a small price compared to the widespread belief that all drug companies put profits ahead of patients. The emphasis is still on finding an approach that will just satisfy demand for change. What's needed is a commitment to high standards, regardless of the commercial impact. - John Carroll

Press Release: The Medicines Company's Cleviprex Phase III Safety Trials Meet Pre-Specified Objectives

Maureen Martino — Tue, 09 Jan 2007 11:09:47 -0500

The Medicines Company's Cleviprex Phase III Safety Trials Meet Pre-Specified Objectives

PARSIPPANY, N.J.--The Medicines Company today announced that its three Phase III safety trials of Cleviprex(TM) (clevidipine) met their pre-specified objectives. Cleviprex is an intravenous, ultrashort-acting calcium channel blocker under development for the treatment of severely elevated blood pressure in the hospital setting when oral therapy is not feasible or desirable. Clive Meanwell, Chairman and CEO of The Medicines Company stated, "With successful completion of this program, we look forward to presentation of the data by investigators. We anticipate submitting an application for Cleviprex U.S. marketing approval in the first half of 2007 and also commencing Phase IV studies of Cleviprex in 2007."

The safety trials, called ECLIPSE, are a series of evaluations enrolling 1,500 patients in the perioperative treatment of hypertension. The three ECLIPSE studies compared Cleviprex to active comparators: nitroglycerin, sodium nitroprusside and nicardipine. For the primary safety objectives, investigators measured the incidences of death, stroke, myocardial infarction and renal dysfunction. The secondary objectives were to evaluate the adverse experiences with Cleviprex and its blood pressure lowering effect. Health economics parameters will also be assessed. The primary data have been reviewed with investigators and a full presentation of the trials is expected at a medical meeting in the first quarter of 2007.

If approved for marketing, Cleviprex IV emulsion would be the first of a third generation of intravenous dihydropyridine calcium channel blockers. It acts by selectively relaxing the smooth muscle cells that line small arteries, resulting in widening of the artery and reduction of blood pressure with minimal effect on the heart rate.

About The Medicines Company: The Medicines Company meets the demands of the world's most advanced medical practitioners by developing products that improve acute hospital care. The Company markets Angiomax® (bivalirudin) in the U.S. and other countries for use in patients undergoing coronary angioplasty, a procedure to clear restricted blood flow in arteries around the heart. The Medicines Company creates value using its range of clinical and commercial skills to develop products acquired from leading life science innovators. The Company's website is http://www.themedicinescompany.com.

Statements contained in this press release about The Medicines Company and Cleviprex that are not purely historical, and all other statements that are not purely historical, may be deemed to be forward-looking statements for purposes of the safe harbor provisions under The Private Securities Litigation Reform Act of 1995. Without limiting the foregoing, the words "believes," "anticipates" and "expects" and similar expressions are intended to identify forward-looking statements. These forward-looking statements involve known and unknown risks and uncertainties that may cause the Company's actual results, levels of activity, performance or achievements to be materially different from those expressed or implied by these forward-looking statements. Important factors that may cause or contribute to such differences include whether the Company's products will advance in the clinical trials process on a timely basis or at all, whether clinical trial results will warrant submission of applications for regulatory approval, whether the Company will be able to obtain regulatory approvals, whether physicians, patients and other key decision makers will accept clinical trial results, and such other factors as are set forth in the risk factors detailed from time to time in the Company's periodic reports and registration statements filed with the Securities and Exchange Commission including, without limitation, the risk factors detailed in the Company's Quarterly Report on Form 10-Q filed on November 8, 2006, which are incorporated herein by reference. The Company specifically disclaims any obligation to update these forward-looking statements.

Contact: The Medicines Company Michael Mitchell, 973-656-1616 Executive Director, Corporate Affairs investor.relations@themedco.com

SPOTLIGHT: India OKs Peregrine trial

Wed, 11 Oct 2006 20:01:33 -0400

India has given Peregrine Pharmaceuticals a green light to conduct clinical trials of its experimental therapy Cotara for a type of brain cancer. "We believe this new clinical trial will be a cornerstone of our future plans to develop Cotara for the treatment of this deadly form of cancer," said Steven W. King, president and CEO of Peregrine. "We are moving this program forward in India because of the high level of experience of the participating neurosurgeons with CED delivery, the state-of-the-art facilities of the medical centers involved and the fact that the contract research organization overseeing the trial is highly experienced in successfully running similar glioblastoma trials with many of the investigators who will be involved with our study." Release

OrthoLogic drug fails in Phase IIb

Tue, 29 Aug 2006 20:01:36 -0400

OrthoLogic has abandoned a multi-dose Phase IIb study of its experimental fracture repair drug Chrysalin after it failed to produce better results than a placebo. Investigators had been testing five different doses of Chrysalin, but determined that patients were not able to remove their casts any quicker after taking the drug. OrthoLogic researchers will now focus on advancing TP508 for fracture repair.

"We interrupted enrollment in the Phase IIb clinical trial in mid-March 2006 in order to perform the interim analysis of subjects enrolled to that date," said Randolph C. Steer, MD, president of OrthoLogic. "This trial was not powered at the interim analysis stage to detect statistically significant differences among dose cohorts regarding the efficacy of Chrysalin. We had hoped to discern a dose response curve through this trial design."

- here's the AP report on the clinical trial failure