Regular 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.
Disclaimer: I have served as a consultant to Zafgen.
Melanocyte-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.
Regular readers will be well aware of the Edmonton Obesity Staging System (EOSS), which classifies individuals living with obesity according to the presence and severity of medical, mental and functional complications on a 5-point ordinal scale.
We have previously shown that EOSS provides a better assessment of mortality risk than BMI, waist circumference, or the presence of metabolic syndrome.
Now, a paper by Sonja Chiappetta and colleagues from Offenbach, Germany, published in SOARD, shows that EOSS strongly predicts early surgical complications and mortality in patients undergoing bariatric surgery.
The authors analysed data from 534 patients, collected prospectively, for patients undergoing laparoscopic sleeve gastrectomy (LSG), laparoscopic Roux-en-Y gastric bypass (LRYGB), or laparoscopic omega-loop gastric bypass (LOLGB).
As typical for a bariatric surgery population, the mean BMI was around 50 kg/m2.
While the total postoperative complication rate for the entire patient sample was 9%, the complications rates were 0% for patients with EOSS Stage 0 (5% of patients), 1.6% for Stage 1 ( (12%), 8% for Stage 2 (71%), 22% for Stage 3 (13%) and 100% for Stage 4 (0.2%).
There was no significant difference in BMI levels across EOSS stages and not consistent association of EOSS stage with age.
From these findings the authors conclude that,
“Patients with EOSS≥3 have a higher risk of postoperative complications. Our data confirm that the EOSS is useful as a scoring system for the selection of obese patients before surgery and suggest that it may also be useful for presurgical stratification and risk assessment in clinical practice. Patients should be recommended for obesity surgery when their EOSS stage is 2 to prevent impairments associated with metabolic disease and to reduce the risk of postoperative complications.”
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.
Continuing in my miniseries on arguments that support calling obesity a disease, is the simple fact that, once established, it behaves like a chronic disease.
Thus, once people have accumulated excess or abnormal adipose tissue that affects their health, there is no known way of reversing the process to the point that this condition would be considered “cured”.
By “cured”, I mean that there is a treatment for obesity, which can be stopped without the problem reappearing. For e.g. we can cure an ear infection – a short course of antibiotics and the infection will resolve to perhaps never reappear. We can also cure many forms of cancer, where surgery or a bout of chemotherapy removes the tumour forever. Those conditions we can “cure” – obesity we cannot!
For all practical purposes, obesity behaves exactly like every other chronic disease – yes, we can modify the course or even ameliorate the condition with the help of behavioural, medical or surgical treatments to the point that it may no longer pose a health threat, but it is at best in “remission” – when the treatment stops, the weight comes back – sometimes with a vengeance.
And yes, behavioural treatments are treatments, because the behaviours we are talking about that lead to ‘remission’ are far more intense than the behaviours that non-obese people have to adopt to not gain weight in the first place.
This is how I explained this to someone, who recently told me that about five years ago he had lost a substantial amount of weight (over 50 pounds) simply by watching what he eats and maintaining a regular exercise program. He argued that he had “conquered” his obesity and would now consider himself “cured”.
I explained to him, that I would at best consider him in “remission”, because his biology is still that of someone living with obesity.
And this is how I would prove my point.
Imagine he and I tried to put on 50 pounds in the next 6 weeks – I would face a real upward battle and may not be able to put on that weight at all – he, in contrast, would have absolutely no problem putting the weight back on.
In fact, if he were to simply live the way I do, eating the amount of food I do, those 50 lbs would be back before he knows it.
His body is just waiting to put the weight back on whereas my biology will actually make it difficult for me simply put that weight on.
This is because his “set-point”, even 5 years after losing the weight, is still 50 lbs higher than my “set-point”, which is around my current weight (the heaviest I have ever been).
Whereas, he is currently working hard against his set-point, by doing what he is doing (watching what he eats, following a strict exercise routine), I would be working against my set-point by having to force myself to eat substantially more than my body needs or wants.
That is the difference! By virtue of having had 50 lb heavier, his biology has been permanently altered in that it now defends a weight that is substantially higher than mine.
His post-weight loss biology is very different from mine, although we are currently at about the same weight.
This is what I mean by saying he is in “remission”, thanks to his ongoing behavioural therapy.
Today, we understand much of this biology. We understand what happens when people try to lose weight and how hard the body fights to resist weight loss and to put the weight back on.
This is why, for all practical purposes, obesity behaves just like every other chronic disease and requires ongoing treatment to control – no one is ever “cured” of their obesity.
Not even people who have bariatric surgery – reverse the surgery and before you know it, the weight is back.
So, if for all practical purposes, obesity behaves like a chronic disease, why not just call a spade a spade?
For an illustration on why obesity acts like a chronic disease watch this short TEDx talk