A slimming drug that actually works?

Slimming with no diet or surgery – but not snake oil??

Yes, actually this really is a cure for obesity. It works and is undergoing clinical trials at the moment. You don’t have to believe it – look up the research referenced below.

Nothing that works is without side effects, so this article considers possible problems that there might be with this wonderful cure for a massive problem (if you excuse the pun!). It is worth mentioning that the author has no links to Zafgen, the original researchers, the Venture Capitalists or any other interested party. Also, the author is a strong supporter of this drug as, almost certainly, the best cure for this epidemic that has been discovered.

The cure is simple, you’ll take a drug over a few months and loose up to a third of your body weight, with no need for diet, exercise or surgery. Amazing, but true. The weight should stay off, maybe not for life, but certainly for a long time.

History

It's been claimed many, many times before, and huge amounts of money have been made pretending that a cure has been found to obesity. Snake oil of all sorts has been poured into the slimming industry, all to no avail. People might lose weight for a while, though taking up horrible slimming diets, exercising to unhealthy excess or any of a number of even crazier notions - liposuction, for one, sucking superficial fat out of the body with a vacuum cleaner.

Then, back in 2004, Mikhail Kolonin, made the break that would become the magic bullet of the 21st Century. His paper 'Reversal of obesity by targeted ablation of adipose tissue' can be found here http://www.nature.com/nm/journal/v10/n6/abs/nm1048.html - Kolonin had been researching a method of curing cancer and had the brilliant idea that it might work for obesity.

His research was funded by a charity that was not in a position to exploit this breakthrough, and so it sold it to a company called Zafgen (www.zafgen.com) that is handsomely funded by a group of Venture Capitalists. Zafgen hope to have the results of the first Clinical Trials early in 2010.

How will this Silver Bullet cure obesity?

All the cells in our body go through a natural life cycle. For us to be healthy, they cooperate with the rest of the body, so much so that, when the body asks them to die, they do. When this cooperative mechanism breaks down, and cells refuse to die when asked, we develop cancer.

The natural death of cells is called apoptosis. The request is made by messages encoded in chemicals called peptides. Kolonin's team had been producing peptides that were aimed (targeted as in his article title) at the blood supply (vasculature) of cancers. Kill the blood supply and the cancer dies. That was the idea. Turning this to fat, he found a peptide that, in mice, would kill the blood supply to their white fat deposits (we have brown [good generally speaking] and white [not good in quantity] fat in our bodies. They used specially bred genetic mice that grow hugely obese and, with this method, they were able to get them to loose a third of their body weight in a few weeks and, apparently remain perfectly healthy. The method is particularly good as it removes fat from around the vital organs (liver, heart, stomach) not just external fat (as something like liposuction does).

To adapt this to people, the right peptide messenger had to be developed and then carefully tested to make sure that it did not, for example, damage the brain (which is quite a fatty organ because the brain uses a lot of energy to think). Zafgen has been working to do this, and the clinical trials should show if it works and if there are any unexpected and dangerous side effects.

The Obesity Epidemic and profit


According to the World Health Organisation (WHO) there are over a milliard people who are defined as ‘obese’ on the planet. Each one of these is a possible target for this drug. So you can see why the Venture Capitalists have been piling in to fund this. If the drug sells for only $10 a treatment, then the research, manufacturing, distribution will be paid for easily, and Zafgen and its backers will be extremely rich.

Danger 1: Marketing and off-label prescribing

That’s not how it is likely to play out though. The literature on Zafgen’s site suggests that only the extremely clinically obese will be targeted for treatment to begin with. This makes sense, for them obesity is not just a life-threatening condition; it reduces the quality of life hugely, so it is only right that they should benefit from this huge breakthrough.

Also, since these patients are already at high risk of death and disease, because of their weight, they are unlikely to be able to sue Zafgen if something seems to have gone wrong. How, the lawyers will ask, can they prove that it’s the slimming drug and not one of the many obesity related conditions that has led to their death or deterioration? A difficult case to prove.

So it’s safe too, from a legal risk perspective.

What’s the problem then?

Well, to sell the drug to just this group of people, Zafgen can apply to the FDA, and other drug licensing bodies, for a license for the drug that states that it is only for use in people who are extremely obese – and only tested on such people.

Now, if this license is granted, and on these narrow terms, what is actually going to happen?

Obviously, literally millions of people will want the drug and will pester their doctors to get it for them. Their doctors are likely to comply and order the drug. But they won’t be able to prescribe it, as licensed, to people who are simply a little overweight, or want it to slim down to get that acting part, or to keep their pilot’s license when they’re not even classified as overweight, let alone obese.

So, will the drug be refused? No. The doctors will be able to do what is known as off-label prescribing. Based on what is called their ‘clinical judgment’ they will be allowed to prescribe the drug as for ‘off-label use’.

What’s the problem with this? The patients get the drug.

The problem is liability. Since the drug is prescribed ‘off-label’, if anything goes wrong, it’s not Zafgen who will be prosecuted, or the FDA for that matter, they’ve only claimed that it will work for extremely obese patients. Patients who have dangerous side effects will only be able to sue their doctor.

This is good news for Zafgen and the Venture Capitalists. Even though ‘off-label’ patients are not benefitting from, or protected by, the research and clinical trials (because they were only designed to test the target group), they won’t get a discount. They will still have to pay full price to Zafgen. So Zafgen gets a risk-free profit. Very nice indeed!

Not good news for patients. The doctor may not have the insurance cover to compensate for the problems – and the problems won’t be listed as side-effects of the drug, because they only apply to ‘off-label’ use. So a major side-effect might be hidden for quite some time, allowing even more people to suffer from it.

So, if you are not in the target group, you have good reason to fear being prescribed the drug off-label – there might be some terrible side effect, that doesn’t happen to extremely obese people, but does to those of more normal weight. You will be, in effect, the guinea pig when you take the drug – but you won’t be part of a proper trial, so, if you die, or are made ill, it won’t contribute to saving other people from taking the drug in the wrong circumstances.

Danger 2: What might these side-effects be?

The short, and truthful, answer is that we won’t actually know until thousands of people have suffered them. We can only speculate on possible side effects, knowing how the drug works. So, speculating, what might these be? Here’s a list of some possibilities, it is not exhaustive:

1. Need for surgery. Rapid, and extreme, weight-loss can leave the skin hanging loosely from the body, and this loose skin can be prone to infections. This effect is found in people who loose weight through bariatric surgery today. The cure is surgery to cut away the excess skin. This surgery is expensive and, like all surgery, risky. So you might pay your $10 (or, more likely $2000 – the Venture Capitalists are unlikely to charge a price related to the cost of the drug, they’ll want to charge as much as the market can stand), but then find that you’re exposed to costs of $30,000 or more for the surgery.
2. Depression and Suicide. Loosing weight can reduce the amount of serotonin in your body, which can lead to depression. If somebody is susceptible to depression already, this could lead to suicides. If the drug is used off-label, the risk is likely to be different from that of the extremely obese patients the drug has been licensed for. So it is possible that some groups might show high levels of suicide that would only be discovered some time later – again because of the off-label prescribing.
3. Drug and vitamin overdoses. Many drugs, including illegal recreational drugs, are stored in fat tissue. When fat is released in large quantities, suddenly, these dissolved substances are likely to be released into the body, potentially in large quantities. Cannabis, for example, is stored in body fat for many days, possibly weeks, after use. This stored drug could suddenly be released, leading to an intense and unexpected ‘trip’ that could arrive suddenly and be dangerous if somebody was, say, driving. Also fat-soluble vitamins would be released, such as Vitamin A [or other fat soluble vitamins [A, D, E & K], which can be lethal to the liver in large quantities, as those who have eaten Polar Bear liver have discovered – so deaths may result from this effect, particularly in people who may have been taking large doses of vitamins over preceding months.
4. Accidental overdose. In theory, the drug will continue to kill off white fat cells until there are none left. Brilliant, you might think, that would suit me! However, we need a certain amount of fat to keep our brain supplied with energy, as well as a reserve for energy needed for other exercise. If we had no white fat, we’d be in danger of a few things, high vulnerability to cold, extreme fatigue, possible black-outs that could only be fixed by eating throughout the day, maybe even needing to wake up at night to eat to keep energy levels up. The problem, again, is that dosage levels will be known and documented for extremely obese patients, but not for the general population or for those who are slightly overweight, so there is a danger, if the narrow licensing model is chosen, of accidental overdose where doctors, unfamiliar with the drug, give higher doses than required. There is also the danger of abuse, where somebody uses the drug prescribed for somebody else and gets an overdose inadvertently. It is not known if this effect would be reversible. It is worth noting that people who take too much will have hardly anything in the bottom and breast department, a side effect that most women would not find desirable.

What is to be done?

As stated at the start, this is intended to be a positive article, not just doom and gloom. So there are potential remedies. The first is for Zafgen to apply for a broadly based license that includes people who are not grossly obese, but only slightly overweight.

If this is not possible, the FDA should require Zafgen to sell the drug at cost, with no profit, if it is prescribed off-label. This would provide Zafgen with a strong incentive to broaden the license as soon as possible.
The FDA should also create a register of off-label effects, not just for this drug, but for all drugs, so that doctors who choose to prescribe drugs off-license can, along with their patients and the symptoms they have, be tracked.

Finally, the risks outlined here, and other likely ones, should be specifically tested with animal models and humans before registration of the drug.

©Copyright Peter Brooks 2009 - contact peter.h.m.brooks@gmail.com for permissions