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.”
Next in my miniseries on the pros and cons of calling obesity a ‘disease’, I turn to the issue of medical education.
From the first day in medical school, I learnt about diseases – their signs and symptoms, their definitions and classifications, their biochemistry and physiology, their prognosis and treatments.
Any medical graduate will happily recite the role and function of ADH, ATP, ANP, TSH, ACTH, AST, ALT, MCV and a host of other combinations of alphabet soup related to even the most obscure physiology and function – everything, except the alphabet soup related to ingestive behaviour, energy regulation, and caloric expenditure.
Most medical students and doctors will never have heard of POMC, α-MSH, PYY, AgRP, CART, MC4R, or any of the well studied and long-known key molecules involved in appetite regulation. Many will have at best a vague understanding of RMR, TEE, TEF, or NEAT.
The point is, that even today, we are graduating medical doctors, who have at best a layman’s understanding of the complex biology of appetite and energy regulation, let alone a solid grasp of the clinical management of obesity.
Imagine a medical doctor, who has never heard of β-cells or insulin or glucagon or GLUT4-transporters trying to manage a patient with diabetes.
Or a medical doctor, who has never heard of renin or aldosterone or angiotensinogen or angiotensin 2 trying to manage your blood pressure.
How about a medical doctor, who has never heard of T3 or T4 or TSH managing your thyroid disease?
Elevating obesity to a ‘disease’ means that medical schools will no longer have an excuse to not teach students about the complex sociopsychobiology of obesity, its complications, prognosis, and treatments.
As I mentioned in a previous post, suddenly, managing obesity has become their job.
No longer will it be acceptable for doctors to simply tell their patients to control their weight, with no stake in if and how they actually did it.
Thus, if there is just one thing that calling obesity a ‘disease’ can change, it is expecting all health professionals to have as much understanding of obesity as they are currently expected to have of diabetes, heart disease, lung disease, and any other common disease they are likely to encounter in their medical practice.
Apparently, simply treating obesity as a ‘lifestyle’ problem or ‘risk factor’ was not enough – hopefully, recognising obesity as a ‘disease’ in its own right, will change the attention given to this issue in medical training across all disciplines.
Next, in my miniseries on arguments to support calling obesity (defined as excess or abnormal body fat that affects your health), I turn to the impact on health care providers.
Currently, most health care practitioners will happily limit their role in obesity management to warning their patients about the many health consequences of carrying excess weight and advise them to lose weight. They do not, however, see it as their job to actually provide treatment.
This is in stark contrast to diabetes or hypertension, where doctors do see helping patients control their blood glucose or blood pressure levels as an essential part of their job. Here, simply telling patients that they need to lower their blood glucose or blood pressure would not be deemed enough. Helping patients control their blood glucose or blood pressure, happens to be an important part of their job description.
One reason that health care providers have gotten away with simply telling patients to lose weight without actually helping them do so, is precisely because they have never viewed obesity as a disease. Rather, they (as much of the public) have looked at excess weight (and weight loss) as simply a matter of personal “lifestyle” – something that people with obesity should be able to manage on their own.
This, incidentally is one of the main reasons why many doctors are not happy with obesity being called a disease. I have actually heard a colleague ask me, “Why should this be my job? Why can’t they (sic) just eat less and move more – how difficult can that be?”.
That, is exactly the attitude adjustment that calling obesity a chronic disease can change. Perhaps not in the generation of doctors and other health professionals who have grown up thinking of obesity as a “lifestyle choice”. But hopefully, in the next generation of health care providers, for whom treating and helping their patients manage their obesity will be no different from treating and helping patients living with any other chronic disease.