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Zafgen Abandons Belanorib Program But Continues Exploring MetAP2 Inhibitor For Obesity

sharma-obesity-insulin-injectionRegular readers may recall previous posts on the novel anti-obesity compound belanorib, a MetAP2 inhibitor that showed remarkable weight loss efficacy both in patients with Prader-Willi Syndrome as well as hypothalamic obesity.

Unfortunately, as noted before, several cases of venous thromoboembolisms led to a halt of ongoing trials during which the company (Zafgen) sought to better understand the possible mechanism for this serious adverse effect and explore the possibility of implementing a risk mitigation strategy.

As announced by the company in a press release earlier this week,

“Following its discussions with the FDA and review of other considerations, Zafgen has determined that the obstacles, costs and development timelines to obtain marketing approval for beloranib are too great to justify additional investment in the program, particularly given the promising emerging profile of ZGN-1061. The Company is therefore suspending further development of beloranib in order to focus its resources on ZGN-1061.”

The press release also describes the new compound ZGN-1061 as a,

“…fumagillin-class, injectable small molecule second generation MetAP2 inhibitor that was discovered by Zafgen’s researchers and has been shown to have an improved profile relative to previous inhibitors in the class. Like other MetAP2 inhibitors that have shown promise in the treatment of metabolic diseases including severe and complicated obesity, ZGN-1061 modulates the activity of key cellular processes that control the body’s ability to make and store fat, and utilize fat and glucose as an energy source. ZGN-1061 is also anticipated to help reduce hunger and restore balance to fat metabolism, enabling calories to once again be used as a productive energy source, leading to weight loss and improved metabolic control. ZGN-1061 has an emerging safety profile and dosage form that are believed to be appropriate for the treatment of prevalent forms of severe and complicated obesity, and is currently in Phase 1 clinical development. Zafgen holds exclusive worldwide rights for the development and commercialization of ZGN-1061.”

According to the press release,

“The compound has similar efficacy, potency, and range of activity in animal models of obesity as beloranib, but displays highly differentiated properties and a reduced potential to impact thrombosis, supporting the value of the compound as a more highly optimized MetAP2 inhibitor.”

Screening of patients for a Phase 1 clinical trial evaluating ZGN-1061 for safety, tolerability, and weight loss efficacy over four weeks of treatment is currently underway.

@DrSharma
Edmonton, AB

Disclaimer: I have served as a consultant to Zafgen.

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Fructose-Sweetened Beverages Do Not Promote Systemic Inflammation

sharma-obesity-beveragesThere is little doubt that increased consumption of fructose-sweetened beverages can be a substantial source of extra calories, thereby potentially promoting weight gain.

That said, fructose has also been implicated in non-caloric metabolic effects including promoting insulin resistance and systemic inflammation.

Now a study by Jessica Kuzma and colleagues from the Fred Hutchinson Cancer Research Center, Seattle, WA, published in the American Journal of Clinical Nutrition, specifically addresses the hypothesis that fructose-sweetened beverages can promote systemic inflammation.

For their study, they randomised 24 otherwise healthy participants to three 8 day periods during which participants consumed 4 daily servings of fructose-, glucose-, or HFCS-sweetened beverages accounting for 25% of estimated calorie requirements while consuming a standardized diet ad libitum.

During the study subjects consumed 116% of their estimated calorie requirement while drinking the beverages with no difference in total energy intake or body weight.

Neither fasting plasma concentrations of C-reactive protein or IL-6 changed during the study.

Furthermore, there were no consistent changes in measures of adipose tissue inflammation or in intestinal permeability.

Overall, the researchers conclude that consuming an excessive amount of fructose, HFCS, and glucose derived from SSBs consumed, at least in the short term (8 days), does not appear to promote systemic inflammation in otherwise healthy adults.

Obviously, this study does not address the issue of wether or not overconsumption of sugar-sweetened beverages can promote obesity or whether cutting out such beverages has any other advantages short of lowering caloric consumption.

@DrSharma
Edmonton, AB

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Arguments For Calling Obesity A Disease #2: It Is Driven By Biology

feastContinuing in my miniseries on reasons why obesity should be considered a disease, I turn to the idea that obesity is largely driven by biology (in which I include psychology, which is also ultimately biology).

This is something people dealing with mental illness discovered a long time ago – depression is “molecules in your brain” – well, so is obesity!

Let me explain.

Humans throughout evolutionary history, like all living creatures, were faced with a dilemma, namely to deal with wide variations in food availability over time (feast vs. famine).

Biologically, this means that they were driven in times of plenty to take up and store as many calories as they could in preparation for bad times – this is how our ancestors survived to this day.

While finding and eating food during times of plenty does not require much work or motivation, finding food during times of famine requires us to go to almost any length and risks to find food. This risk-taking behaviour is biologically ensured by tightly linking food intake to the hedonic reward system, which provides the strong intrinsic motivator to put in the work required to find foods and consume them beyond our immediate needs.

Indeed, it is this link between food and pleasure that explains why we would go to such lengths to further enhance the reward from food by converting raw ingredients into often complex dishes involving hours of toiling in the kitchen. Human culinary creativity knows no limits – all in the service of enhancing pleasure.

Thus, our bodies are perfectly geared towards these activities. When we don’t eat, a complex and powerful neurohormonal response takes over (aka hunger), till the urge becomes overwhelming and forces us to still our appetites by seeking, preparing and consuming foods – the hungrier we get, the more we seek and prepare foods to deliver even greater hedonic reward (fat, sugar, salt, spices).

The tight biological link between eating and the reward system also explains why we so often eat in response to emotions – anxiety, depression, boredom, happiness, fear, loneliness, stress, can all make us eat.

But eating is also engrained into our social behaviour (again largely driven by biology) – as we bond to our mothers through food, we bond to others through eating. Thus, eating has been part of virtually every celebration and social gathering for as long as anyone can remember. Food is celebration, bonding, culture, and identity – all features, the capacity for which, is deeply engrained into our biology.

In fact, our own biology perfectly explains why we have gone to such lengths to create the very environment that we currently live in. Our biology (paired with our species’ limitless creativity and ingenuity) has driven us to conquer famine (at least in most parts of the world) by creating an environment awash in highly palatable foods, nutrient content (and health) be damned!

Thus, even without delving any deeper into the complex genetics, epigenetics, or neuroendocrine biology of eating behaviours, it is not hard to understand why much of today’s obesity epidemic is simply the result of our natural behaviours (biology) acting in an unnatural environment.

So if most of obesity is the result of “normal” biology, how does obesity become a disease?

Because, even “normal” biology becomes a disease, when it affects health.

There are many instances of this.

For example, in the same manner that the biological system responsible for our eating behaviour and energy balance responds to an “abnormal” food environment  by promoting excessive weight gain to the point that it can negatively affect our health, other biological systems respond to abnormal environmental cues to affect their respective organ systems to produce illnesses.

Our immune systems designed to differentiate between “good” and “bad”, when underexposed to “good” at critical times in our development (thanks to our modern environments), treat it as “bad”, thereby creating debilitating and even fatal allergic responses to otherwise “harmless” substances like peanuts or strawberries.

Our “normal” glucose homeostasis system, when faced with insulin resistance (resulting from increasingly sedentary life circumstances), provoke hyperinsulinemia with ultimate failure of the beta-cell, resulting in diabetes.

Similarly, our “normal” biological responses to lack of sleep or constant stress, result in a wide range of mental and physical illnesses.

Our “normal” biological responses to drugs and alcohol can result in chronic drug and alcohol addiction.

Our “normal” biological response to cancerogenous substances (including sunlight) can result in cancers.

The list goes on.

Obviously, not everyone responds to the same environment in the same manner – thanks to biological variability (another important reason why our ancestors have made it through the ages).

But, you may argue, if obesity is largely the result of “normal” biology responding to an “abnormal” environment, then isn’t it really the environment that is causing the disease?

That may well be the case, but it doesn’t matter for the definition of disease. Many diseases are the result for the environment interacting with biology and yes, changing the environment could indeed be the best treatment (or even cure) for that disease.

Thus, even if pollution causes asthma and the ultimate “cure” for asthma is to rid the air of pollutants, asthma, while it exists, is still a disease for the person who has it.

All that counts is whether or not the biological condition at hand is affecting your health or not.

The only reason I bring up biology at all, is to counter the argument that obesity is simply stupid people making poor “choices” – one you consider the biology, nothing about obesity is “simple”.

@DrSharma
Edmonton, AB

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Arguments Against Obesity As A Disease #9: Its Just A Risk Factor

sharma-obesity-blood-pressure4Next, in my miniseries on arguments I commonly hear against the notion of calling obesity a disease, is that it is “just a risk factor” for other diseases.

This may be true, if you just (wrongly) considered elevated BMI as your definition of obesity, because no doubt, people with higher BMI levels carry a higher risk for obesity related complications including type 2 diabetes, sleep apnea, fatty liver disease, hypertension – just to name a few. (Note that increased risk is not the same as actually having the condition!).

However, when you use the actual WHO definition of obesity, namely, “accumulation of excess or abnormal fat that impairs health”, obesity is no longer just a risk factor – it is now (by definition) impairing your health, which makes it far more than just a risk factor.

So while someone with a BMI of 35 may be at risk of developing obesity (not the same as having it), when their excess fat actually starts impairing their health, it de facto becomes a disease in its own right.

Even then, one might argue that obesity itself is not the disease, rather the complications of obesity are the real disease.

This notion is both right and wrong.

There are many conditions that are both diseases in their own right as well as risk factors for other diseases or complications.

Take type 2 diabetes for instance – it is both a disease in itself but also a risk factor for coronary heart disease or end-stage kidney disease.

Take hypertension – a disease in its own right but also a risk factor for strokes and heart attacks.

Take gastro-oesophageal reflux disease, which is also a risk factor for Barrett’s disease and oesophageal cancer.

Take fatty liver disease, which is also a risk factor for cirrhosis.

Gall bladder stones, which is also a risk factor for pancreatitis.

Multiple sclerosis, which is also a risk factor for neurogenic bladder and pyelonephritis.

The list goes on and on.

So just because obesity is also a risk factor for a wide range of other medical problems, it does not make obesity any less of a disease in its own right.

When excess or abnormal body fat affects health – it’s a disease. When it doesn’t, it’s at best a risk factor.

That, is perhaps a subtle but important distinction.

@DrSharma
Toronto, ON

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Arguments Against Obesity As A Disease #2: Inconsistent Relationship Between Body Fat And Health

scatterplot variationYesterday, in my brief series on the pros and cons of calling obesity a chronic disease, I addressed the issue of BMI as a poor definition of obesity (understood here as “abnormal or excess body fat that affects health”).

Another common argument I hear from those who do not support the notion of obesity as a chronic disease, is that there is an inconsistent relationship between body fat and health.

This is no doubt the case.

Indeed, whether or not your body fat affects your health depends on a range of factors – from your genetic predisposition to certain “complications” to the “nature” of your body fat, factors that cannot be captured or assessed by simply stepping on a scale.

Often, this variability in the relationship between excess body fat and its impact on health, is used to argue against a “causal relationship” between the two. This argument is often presented along the lines of, “If obesity is a disease, how come I don’t have diabetes?”.

Where the direct impact of excess body fat on health should be evident,  is when the amount of excess fat poses a direct “mechanical” problem that impedes physical functioning. This impact, however, is likely to vary from one person to the next.

A good example of this, is obstructive sleep apnea, where an increase in pharyngeal fat deposition is directly and causally related to the airway obstruction. The causal relationship of pharyngeal fat and the symptoms is directly evident by improvement in symptoms following surgical removal of the excess fat (an operation that is seldom undertaken due to possible complications and redeposition of fat). There is also substantial evidence that significant weight loss (such as induced by bariatric surgery) results in a dramatic improvement in apnea/hypopnea index and sometimes even in complete resolution of the problem.

Yet, not everyone with excess weight develops obstructive sleep apnea. One of the factors that explains this variation, is the anatomical dimension of the pharyngeal space, which varies significantly from one person to the next. So, just how much excess fat in the neck region results in symptoms (if any) will necessarily be highly variable. This is not an argument against the relationship between excess body fat and obstructive sleep apnea, it is just the expected variation between individuals that is evident in many diseases.

Likewise, when the amount of excess fat impairs the body’s capacity to perform essential functions (from mobility to performing simple tasks of personal hygiene), it is not a matter of “opinion” whether obesity is the cause of the problem. There is however variation in how people perceive these “limitations” as limitations, which explains why there may well be considerable variation and inconsistncy in the objective vs. subjective impact of excess body fat on physical functioning.

The relationship between excess or abnormal body fat and metabolic problems is perhaps less easy to understand but biologically as evident. Thus, there is an almost linear relationship between the presence of visceral fat and the risk for diabetes. This risk is greatly amplified in individuals with a family history of diabetes. Thus, the amount of visceral fat necessary to impair glucose homeostasis varies from one person to the next and depends on other factors including beta-cell capacity to produce insulin.

Note that I said “visceral” fat rather than body fat. This is because subcutaneous fat appears to have little (if any) effect on diabetes risk and may even be protective. Thus, it is not the total amount of body fat but rather its location and biological function that determines its effect on metabolic disease. Therefor, it is easy to see why there would be an inconsistent relationship between body fat (or even cruder measures such as BMI) and risk for diabetes.

There is also considerable evidence that the metabolic effects of excess body fat can be substantially modified by cardiorespiratory fitness (“fat but fit” vs. “lean but unfit”). This is in part because although exercise does not necessarily reduce overall body fat, it appears to have a very specific effect on visceral fat. Moreover, increased muscle mass appears to neutralise some of the metabolic consequences of excess body fat. While all of this is true, it does not negate the fact that visceral fat remains one of the key drivers of metabolic risk, even if there remains substantial variations in how much this risk translates into severe health problems for a given individual.

Even more difficult to understand is the relationship between excess body fat and its impact on mental health. This is particularly difficult because the emotional impact of excess weight also very much depends on the social context. Clearly, the impact of body shape and size on health and well-being will be different across societies that are more or less accepting of larger bodies.

Nevertheless, social context does not obviate the fact that excess body fat can significantly affect mental health in a given individual living in a given societal context. Indeed, there are numerous instances where the “environment” defines or amplifies the effect of biological variations on health. The most extreme example I can think of would be a peanut allergy. While this may have no impact whatsoever on the health of someone living in a nut-free environment, it can be fatal to someone living in a society where peanuts are found in almost every dish (e.g. Thailand).

Thus, despite variation in the relationship between body fat% or BMI and health, including the fact that this relationship may vary depending on societal or environmental context, is not really an argument against obesity as a disease.

All that matters for the definition of obesity as a chronic disease is whether or not a person’s physical, emotional or functional health is affected by excess or abnormal body fat – that this varies between individuals is only to be expected.

Indeed, the impact of many diseases on health can be substantially modified by environmental factors or social context (e.g. diabetes, heart disease, depression) – this does not prevent us from calling them diseases.

Similarly, the actual impact of many disease on an individual’s health can vary widely between individuals – this does not make them more or less of a disease.

In fact, I would claim that there is an “inconsistent” relationship between virtually every disease and morbidity and mortality at the level of the individual – from depression to cancer, from pneumonia to Alzheimer’s.

Thus, inconsistencies in the relationship between body fat and its impact on health across a population, does not speak against the notion that when excess or abnormal body fat negatively affects a given individual’s health, it should be considered a chronic disease.

@DrSharma
Berlin, Germany

 

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