Now Rhythm Pharmaceuticals released its first data on the use of their novel MC4-R agonist setmelanotide in patients with obesity and proven MC4-R defects.
According to their press release,
“In this pilot study, obese (BMI >/= 30kg/m2) patients with a heterozygous MC4R loss-of-function mutation were enrolled in a double-blind, placebo-controlled, randomized, parallel-group study for 4 weeks. Eight patients (six active, two placebo) received placebo or RM-493 at 0.01 mg/kg/day (~ 1 mg/day) by continuous subcutaneous infusion. Key endpoints were safety, weight loss, waist circumference, and caloric intake. Setmelanotide was well tolerated over 4 weeks, with no serious adverse events or discontinuations. The most common side effects were headache and skin tanning, with the latter believed to be due to off-target activity at the related melanocortin-1 receptor. Setmelanotide demonstrated strong trends for placebo-subtracted weight loss (2.62 kg; p=0.088); WC (5.1 cm; p=0.188) and daily caloric intake (351 kCal/day; p=not significant), without clinically important effects on heart rate or blood pressure.”
Overall, the company has taken (the perhaps wise) option of focussing their development program on genetic forms of obesity.
Currently they have an ongoing Phase 2 setmelanotide trial for the treatment of Prader-Willi syndrome and a second Phase 2 trial for the treatment of pro-opiomelanocortin (POMC) deficiency obesity, a very rare, life-threatening genetic disorder of the MC4 pathway associated with unrelenting appetite and obesity.
Clearly, this will be a space to watch.
As Canada’s national representative in the World Obesity Federation (formerly IASO), the Canadian Obesity Network is proud to co-host the 13th International Congress on Obesity in Vancouver, 1-4 May 2016.
The comprehensive scientific program will span 6 topic areas:
Track 1: From genes to cells
- For example: genetics, metagenomics, epigenetics, regulation of mRNA and non–coding RNA, inflammation, lipids, mitochondria and cellular organelles, stem cells, signal transduction, white, brite and brown adipocytes
Track 2: From cells to integrative biology
- For example: neurobiology, appetite and feeding, energy balance, thermogenesis, inflammation and immunity, adipokines, hormones, circadian rhythms, crosstalk, nutrient sensing, signal transduction, tissue plasticity, fetal programming, metabolism, gut microbiome
Track 3: Determinants, assessments and consequences
- For example: assessment and measurement issues, nutrition, physical activity, modifiable risk behaviours, sleep, DoHAD, gut microbiome, Healthy obese, gender differences, biomarkers, body composition, fat distribution, diabetes, cancer, NAFLD, OSA, cardiovascular disease, osteoarthritis, mental health, stigma
Track 4: Clinical management
- For example: diet, exercise, behaviour therapies, psychology, sleep, VLEDs, pharmacotherapy, multidisciplinary therapy, bariatric surgery, new devices, e-technology, biomarkers, cost effectiveness, health services delivery, equity, personalised medicine
Track 5: Populations and population health
- For example: equity, pre natal and early nutrition, epidemiology, inequalities, marketing, workplace, school, role of industry, social determinants, population assessments, regional and ethnic differences, built environment, food environment, economics
Track 6: Actions, interventions and policies
- For example: health promotion, primary prevention, interventions in different settings, health systems and services, e-technology, marketing, economics (pricing, taxation, distribution, subsidy), environmental issues, government actions, stakeholder and industry issues, ethical issues
Early-bird registration is now open – click here
Abstract submission deadline is November 30, 2015 – click here
For more information including sponsorship and exhibiting at ICO 2016 – click here
I look forward to welcoming you to Vancouver next year.
Any form of rapid weight loss is well known to promote the formation of gall stones. Thus, given the rapid rate of weight loss post bariatric surgery, patients are at particularly high risk of developing gall stones (and related complications).
Now, a study by Lindsay Adams and colleagues, published in Obesity Surgery reports on a trial that examined whether or not administration of ursodeoxycholic acid (UDCA) could reduce the incidence of galls stones following sleeve gastrectomy.
75 eligible patients (57 of who completed the study) were randomized to receiving 300 mg UDCA twice daily for 6 months post-surgery or no treatment. Gallbladder ultrasounds were performed preoperatively and at 6 and 12 months postoperatively.
At 6 months, 2 of the 19 treated patients who had ultrasounds had gall stones compared to 10 of 25 patients in the control group.
However, at 12 months (6 months after discontinuation of therapy), 2 of 22 treated patients had galls stones compared to 3 out of 14 in the control group.
Of the 17 patients who developed gallstones, 7 patients underwent cholecystectomy.
Whether or not patients developed sludge or stones with treatment was highly dependent on compliance to treatment. Thus, from those patients who completed the 6-month ultrasounds, neither gallstones nor sludge were reported in any of 11 patients who reported good compliance. Two out of three patients who reported moderate compliance developed gallstones or sludge, and two out of five who reported poor compliance developed gallstones or sludge.
Overall, the authors note that the incidence of gallstones with about 30% was as high as has been reported for patients with gastric bypass surgery.
Clearly this study (as acknowledged by the authors) has important limitations due to the considerable number of participants that were lost to follow-up.
Nevertheless, for what it’s worth, the study certainly suggests that USCA treatment can markedly reduced the incidence of sludge and gallstones at 6 months in patients undergoing sleeve gastrectomy.
As to whether or not this would justify the routine use of USCA in all patients following bariatric surgery is certainly debatable.
According to a report in JAMA, A bipartisan group of US lawmakers has introduced House and Senate versions of the same bill, the Treat and Reduce Obesity Act of 2015, intended to help reduce health care costs and decrease the incidence of chronic disease associated with obesity, including high blood pressure, heart disease, and type 2 diabetes.
The bill calls for not only giving Medicare beneficiaries access to obesity treatments provided by health care practitioners other than primary care physicians, including nurse practitioners, clinical psychologists, and registered dietitians (if referred by a primary care physician) but also to expand drug coverage for obesity treatment under Medicare.
Meanwhile in Canada, accessing evidence-based treatment for obesity, including services offered by dietitians or psychologists as well as access to anti-obesity medications or surgery remains largely elusive to most Canadians living with obesity.
With upcoming federal elections in Canada, I wonder if any political party would step up to declare that continued discrimination against Canadians living with obesity with denial of access to evidence-based treatments is unacceptable (for e.g. obesity treatments are specifically excluded in most third party drug plans in Canada).
Now a small study by Mojca Jensterle and colleagues from Ljubljana, published in the European Journal of Clinical Pharmacology, reports that genetic variability in the GLP-1 receptor gene may predict the variability to the human GLP-1 analogue liraglutide, now approved for obesity treatment in the US, Canada and Europe.
In their study, Jensterle and colleagues examine the realationship between two common alleles (variants) of the GLP-1 receptor in 57 women with obesity and polycystic ovary syndrome.
All women were treated with liraglutide 1.2 mg QD s.c (well under the 3.0 mg QD dose approved for obesity treatment) for 12 weeks.
Twenty of the participants were classified as strong responders (>5% weight loss), who lost about 7.4 Kg, whereas 37 were considered poor responders losing only 2.2 Kg.
Carriers of at least one rs10305420 allele were about 70% less likely to be a high responder than individuals with two wild-type alleles. Similarly, carriers of at least one rs6923761 allele were about three times as likely to high responders compared to homozygous carriers of the wild type.
Although my previous work in these type of genetic studies have made me highly critical (not to say sceptical) of these types of small studies, the notion that genetic variability in the GLP-1 receptor (the molecular target of liraglutide) may well lead to differences in response is not all that far fetched.
Thus, whether true or not, I have little doubt that indeed much of the variability in pharmacological response to liraglutide (or for that matter any other drug for anything) may well be determined by genetics.
Whether testing people for genetic markers before starting a specific treatment will ever become reality for obesity and whether or not, the genetic variability seen in this study will still be seen when lirglutide is used at the actual dose approved for obesity treatment remains to be seen.
In the meantime, the easiest way to see who responds and who does not is to try it. This why the regulatory approval of liraglutide for obesity comes with a simple stopping rule – if it doesn’t work for you – stop taking it!
Disclaimer: I have received consulting and speaking honoraria from Novo Nordisk, the maker of liraglutide.