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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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POMC Mutation Obesity Responds To Melanocortin-4 Receptor Agonist

sharma-obesity-hypothalamusMelanocyte-stimulating hormone (a-MSH), which is produced from the hormone precursor proopiomelanocortin (POMC) and acts on the hypothalamic melanocortin-4 receptor, plays a key role in the regulation of satiety and energy expenditure.

In very rare instances, mutations of the gene coding for POMC can cause severe early onset obesity characterised by increased appetite. Due to other effects of POMC deficiency, patients will present with pale skin, red hair and clinical signs of hypocortisolism.

Now, a paper by Peter Kühnen and colleagues published in the New England Journal of Medicine, shows that treating patients with the melanocortin-4 receptor agonist, setmelanotide, can result in significant reduction in appetite and body weight.

The open-label study was performed in two adult patients with POMC deficiency, in cooperation with Rhythm Pharmaceuticals, which provided the study medication and regulatory support.

Both patients weighed around 150 Kg with marked hyperphagia and both responded to treatment with a substantial reduction in appetite and dramatic weight loss of over 20 Kg over 12-13 weeks.

After a brief interruption, one patient was again treated for 42 weeks, ultimately losing 51 kg (32.9% of her initial body weight).

As the authors note,

“Setmelanotide appeared to completely reverse hyperphagia, leading to impressive weight loss and normalization of insulin resistance. More important, both patients reported a dramatic improvement in their quality of life after the initiation of setmelanotide therapy. Moreover, the substantial and ongoing reduction in body weight was similar to the changes observed after leptin administration in patients with leptin deficiency.”

Over all the treatment was well tolerated with no major adverse effects.

While these observations were made in very rare patients with documented POMC deficiency, these findings may have broader implications for individuals with more common “garden-variety” obesity.

“Both patients described here had very high leptin levels before treatment, suggesting leptin resistance. In patients with proopiomelanocortin deficiency, the leptin signal is probably not properly transduced into anorexigenic responses, given the lack of melanocyte-stimulating hormone. Setmelanotide substitutes for melanocyte-stimulating hormone and binds at its receptor, thus overcoming leptin resistance. On the basis of the observation that obese patients without known genetic abnormalities have severe leptin resistance and regain weight owing to a post-dieting increase in appetite, we speculate that setmelanotide may also be effective in nongenetic forms of obesity.”

Appropriate studies in patients with non-POMC deficient obesity are currently underway.

@DrSharma
Atlanta, GA

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Bariatric Surgery Improves Mitochondrial Efficiency

sharma-obesity-mitochondriaOne of the more frustrating aspects of weight loss, is that it is often associated with decreased metabolic rate and increased ‘fuel efficiency’.

Thus, following weight loss, not only does the body need fewer calories, doing the same amount of physical work uses fewer calories than before (the joke is that, if you ran 5K a day to lose weight, you have to run 10K a day to keep it off).

Now, a study by Maria Fernström and colleagues, published in Obesity Surgery, shows increased mitochondrial efficiency following bariatric surgery.

The researchers performed skeletal muscle biopsies in 11 women before and at 6 months after gastric bypass surgery.

Measurements in isolated mitochondria showed a marked increase in coupled respiration (state 3) and overall mitochondrial capacity (P/O ratio) with a non-significant increase in uncoupled (state 4) respiration.

Thus, at 6 months following gastric bypass surgery, both the mitochondrial capacity for coupled, i.e., ATP-generating, respiration increased as well as the P/O ratio improved.

As the authors note, not only would this increased “fuel efficiency” in part explain the decreased basal metabolism often associated with weight loss but also the propensity for weight regain that often follows weight-loss interventions.

Obviously, due to lack of a control group, this study does not demonstrate that these changes are in any way specific to weight-loss following bariatric surgery.

Also, given that the nadir of weight loss is generally not achieved until about 18 months following surgery, the changes observed in this study may not represent the maximum increase in mitochondrial efficiency to be achieved with further weight loss.

@DrSharma
Edmonton, AB

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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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