DECEMBER 2000/JANUARY 2001 OMR -- GENETICS AND DRUG DEVELOPMENT

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LETTER FROM THE EDITOR.

Over the past year, obesity gene and weight loss drug discovery programs have made much progress. In the Obesity-news annual drugs in development issue last October, we reported the discovery of 11 new genes and 8 drugs in clinical trials. In this issue, we report the start of phase 1 trials on Metabolic Pharmaceuticals weight loss drug AOD9604. And just last month we reported the positive results of phase 2 trials on Axokine and the start of multicenter phase 3 trials later this year.

The good news is there is much more activity in drug development and discovery programs than just a year ago, and improved discovery methods make it likely that the next generation of drugs will be more effective and have fewer side effects than the last. However, it is unlikely we will see any of these drugs on the shelves in anything less than 3-5 years.

In the meantime, we have the old prescription stand-bys, and until recently phenylpropanolamine (PPA), the only over-the-counter (OTC) drug to be FDA approved for weight loss. In addition, OTC ephedra or ephedrine and caffeine combinations also have favorable results.

The bad news is that all stimulant over-the-counter weight loss medications are under attack. In November, the Food and Drug Administration called for the voluntary withdrawal of phenylpropanolamine from the market, based on the results of a Yale University epidemiologic study on PPA and stroke. And the agency continues to assert that herbal ephedra and caffeine combinations are unsafe as regulated under the Dietary Supplement and Health Education Act (DSHEA).

But the real question is how much actual risk is there? The PPA study estimates that one in 107,000 to 3,268,000 women aged 18 to 49 taking PPA-containing appetite suppressants will have a stroke. No one can accurately determine risk for ephedra supplements, but it is also very small. According to the Cantox report, an analysis commissioned by the Council for Responsible Nutrition, 29 adverse event reports on ephedra were filed with the FDA in 1999, and the best guess is that some 12 million individuals took ephedra-containing supplements for a variety of purposes during the same year.

Compare this to the risk profile of penicillin. A Danish study estimated 3 cases per 100,000 in the general population per year.

In a perfect world all drugs and supplements would have a 100 percent safety profile, but reality is that life as we all know it has risks. And so a nagging question remains, are OTC drugs and supplements to treat obesity being targeted? If the safety profile of PPA and ephedra is poor, why hasn't the FDA called hearings on the safety of penicillin and aspirin?

And if you can stand one more statistic, it is estimated that 300,000 individuals die each year of obesity related conditions. As obesity expert George Bray has frequently said, obesity is a major epidemic, and increasing numbers of individuals are affected every year. Until new therapies become available, we need all the help we can get and effective over-the-counter drugs and supplements with a decent safety profile should not be the subject of attack.

Drug studies	Human growth hormone fragment update. New plant extract treats insulin resistance and obesity. Lead candidate for serotonin anti-obesity drug picked. Mechanism for fenfluramine associated heart valve damage proposed. Sibutramine and long term weight maintenance.
Obesity gene discoveries	New gene results in leanness and reverses obesity in leptin deficiency. VNTR: The link between diabetes and obesity. Review article: Ghrelin.
OTC supplements	More on the ephedra controversy. Phenylpropanolamine withdrawal. Other news.
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Metabolic Pharmaceuticals announced that it completed preclinical tests on its obesity drug, AOD9604, in August and is now planning a single dose intravenous phase 1 trial scheduled to begin early February in the UK. The intravenous study will be followed by oral and multiple dose phase 1 studies. AOD9604 is an orally administered peptide variant of hGH 177-191, a small region of the growth hormone molecule which is responsible for lipolysis. It has none of the anabolic effects on muscle and bone, and does not effect insulin sensitivity.

Because of its effects on body fat, growth hormone has been studied extensively as an antiobesity agent. Obese patients given growth hormone have increased energy expenditure and reduced fat mass. On the other hand, patients suffering from growth hormone deficiency are generally obese and short. Levels of growth hormone decline with age, which explains the tendency of most people to gain weight as years advance.

In animal tests and in vitro experiments on human fat, AOD9604 has been shown to produce weight loss similar to that seen with physical exercise. It has the fat reducing effects of intact growth hormone without other unwanted effects, like insulin resistance or bone growth. The drug does not alter food intake.

Previous difficulties with manufacturing AOD9604 have delayed its progress, but those problems have now been overcome. Provided that the phase 1 human study is successful, Metabolic anticipates beginning phase 2 dose-ranging studies later in 2001. The company is also investigating a second generation drug.

For more on the anabolic effects of growth hormone, see growth hormone in obesity in Obesity 101, and coverage of ghrelin in this issue.

The over-the-counter medication phenylpropanolamine (PPA) has been withdrawn from the market following a November 6, 2000 Food and Drug Administration health advisory. PPA is a stimulant which constricts peripheral blood vessels, including those in nasal passages. For this reason, it is used as a decongestant in numerous cold and allergy remedies, including Dimetapp and Tavist D. It is also the primary ingredient in the OTC weight loss medications Dexatrim and Acutrim. In the years 1969 to 1991 the FDA received 22 reports of PPA associated hemorrhagic stroke, bleeding into the brain or into tissue surrounding the brain. Sixteen of those cases were associated with phenylpropanolamine in appetite suppressants and 6 with PPA in cough and cold remedies. As a result, the FDA sought out more information to determine what risks PPA might pose to the general public.

In 1992, Yale University School of Medicine collaborated with the FDA and manufacturers of phenylpropanolamine to design the Hemorrhagic Stroke Project, a case-control study of men and women who were 18 to 49 years of age. The final report of the HSP project, which was carried in the December 21, 2000 issue of the New England Journal of Medicine, found a very low prevalence of hemorrhagic stroke in women using PPA-containing appetite suppressants, and no definitive correlation with cough and flu medications, or in men. Nonetheless, in November the FDA contacted manufacturers of PPA containing products to voluntarily withdraw them from the market.

Hemorrhagic Stroke Project study.
subjects. Investigators recruited 702 patients and 1376 control subjects from 43 US hospitals. Eligibility criteria for patients included the occurrence of a subarachnoid or intracerebral hemorrhage within 30 days before enrollment and the absence of a previously diagnosed brain lesion. For each case subject, two control subjects matched for age, gender, and race were identified.

Methods. Subjects were asked to recall cold symptoms, medications used to treat them, and any other medications taken during the two weeks before the stroke. Brand-name medications were identified from a book containing photographs of packages. When available, patients were asked to produce each medication so that the exact name and manufacturer's lot number could be recorded. If the container was not available, use of a brand-name medication was considered verified if the subject identified it in the book. Case subjects were classified as exposed to phenylpropanolamine if they reported use of the drug within 3 days of having a stroke.

Results.

The results of the study indicate that one of every 107,000 to 3,268,000 women aged 18 to 49 may have a stroke if they use PPA-containing appetite suppressants. There was also a suggestion of an association in women with any first use of phenylpropanolamine in cough or cold remedies. No significantly increased risk of hemorrhagic stroke was found in men who used PPA containing cough or cold remedies. No male subjects reported the use of appetite suppressants containing phenylpropanolamine and only two reported an event after the first use of a product containing phenylpropanolamine. Therefore researchers could not determine whether men were at increased risk for hemorrhagic stroke under those conditions. It should be noted that epidemiologic studies like the HSP are not valuable in estimating individual risk. However, they can be used estimate the number of people who will develop a condition, such as a stroke, after exposure to a risk factor, in this case PPA.

Industry responds.
Although industry did recall PPA-containing products, it clearly did not agree with the FDA's decision. In a written statement Chattem, which manufactures Dexatrim, disagreed with the recommendation of the FDA's Nonprescription Drug Advisory Committee, saying it believes that Dexatrim with PPA is a safe and effective way of treating moderate obesity when taken in accordance with directions.

R. William Soller, PhD, senior vice president and director, Science and Technology at Consumer Healthcare Products Association (CHPA) also blasted the FDA for its decision. In a press release following his testimony at the October 19, 2000 PPA hearings, Soller said, "Based on the weight of the existing scientific evidence and the opinions of leading independent medical experts, PPA is safe and effective when used according to label directions. An independent panel of epidemiologists expressed serious reservations that the [Hemorrhagic Stroke Project] HSP study did not rise to the level of scientific documentation necessary to support the advisory committee opinion reached today. PPA has been clinically studied in over 5,000 patients and in other epidemiologic studies, affirming its benefits and safety as a diet aid for weight control and as a nasal decongestant for symptoms of colds, hay fever, other respiratory allergies, and sinusitis."

"Although recommended doses of PPA have been shown to cause small, transient, but clinically insignificant, changes in blood pressure, these minor changes are within the range of usual increases associated with such daily activities as climbing stairs or mowing a lawn."

The UK's Medicines Control Agency weighs in.
While across the pond, agencies have been much more conservative regarding the use of stimulants, the UK's Committee on Safety of Medicines (CSM) ruled on November 10 that PPA will continue to be available in cold and allergy medications there, commenting that the evidence of a link is weak and mainly associated with indications which are not licensed in the UK (i.e., weight loss). It also proposed the following guidelines:

The standard dose of PPA in over-the-counter weight loss medications, such as Dexatrim, is 75 mg per day.

Kao Corporation has announced that the Food and Drug Administration has given diacylglycerol (DAG) GRAS status (generally recognized as safe). DAG, is the primary ingredient in Kao's Healthy Econa Cooking Oil, which has been sold in Japan since February 1999. DAG prevents postprandial increase in blood triglyceride in addition to preventing fat deposits. Kao is now in discussions with a US partner to launch operations in the US market.

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GENETICS AND DRUG DEVELOPMENT

LETTER FROM THE EDITOR.

Contents

Results.