Sibutramine evaluated in PWS

Individuals with PWS are, in many ways, perfect subjects for studying the effectiveness of candidate obesity drugs. Excessive weight gain is a common and critical issue, frequently leading to a multitude of medical complications. Even in the best of environments and with the best efforts of those with the disorder, maintaining good weight control is a constant struggle. Behavior therapy has been ineffective, given the strong biological drive to eat. Finally, the ability to control hunger has the potential to be life altering, as it may well afford those with PWS new opportunities and independence.

So, why is this not the first population to be studied when new obesity drugs come out?

The reasons are many. Most practically, the PWS population is small, and running a clinical trial in a small population poses significant logistical hurdles. Cognitive impairment may make issues of acquiring "informed consent" (ie, having the study subject truly understand the potential risks and benefits) difficult. Patient compliance is key to having interpretable outcomes in clinical trials, and those with PWS are not always well known for compliance. Existing health issues might predispose those with PWS to more adverse effects. Finally, many with PWS are being simultaneously treated with other drugs, including those for psychiatric illness, and this often pushes them into the "excluded" category, for fear of adverse drug interactions.

Given this litany of obstacles, a new study from Dr. Claude Marcus and colleagues at the Karolinska University in Sweden is very welcome. The article [Danielsonn et al, Impact Sibutramine Therapy on Children with Hypothalamic Obesity or Obesity with Aggravating Syndromes . J Clin Endo Metab 2007] details the findings of a double blind, placebo-controlled, cross-over study to examine the effects of sibutramine (a..k.a, Reductil or Meridia) on weight loss in a population of individuals with syndromes or conditions that predispose them to morbid obesity, including individuals with hypothalamic damage consequent to brain tumors, those with PWS, and those with obesity due to other conditions (for example, the genetic syndrome Laurence Moon Bardet Biedle syndrome) . The patients were defined as having "hypothalamic obesity" (tumor patients, PWS, LMBBS) or nonhypothalamic obesity (autism, mental retardation, etc). The study included 4 individuals with PWS (13-17 years), two of whom were already on serotonin reuptake inhibitors (SSRIs), presumably to manage behavioral difficulties/mood issues. Those on SSRIs were particularly closely followed for any signs of serotonin toxicity.

Sibutramine is a relatively new drug that is thought to enhance satiety by inhibiting the reuptake of neurotrasmitters including serotonin, norepinephrine and dopamine. The study design is stringent - drug and placebo look identical and neither patient nor doctor knows which is which (ie, double blind). Each patient received either drug or placebo first (for 20 weeks) and then "crossed over" to either placebo or drug for another 20 weeks. This was followed by a 6 month period where subjects could continue on sibutramine openly, if they desired.

The results were encouraging, if not blockbuster. Most of the study participants were adolescents or young adults, so measuring weight gain or loss is not informative in a group that is still growing. Instead, the authors looked for changes in the subject's body-mass index scores compared to normal values over time (BMI SDS). In all patients, BMI SDS scores dropped significantly when they were on the drug- keep in mind, for many, this contrasts with a pre-trial trend of increasing BMI. Also, the mechanisms promoting obesity are different across the different syndromes and conditions, so it is notable that the drug was effective in all. For those who started on the drug and switched to placebo, a rebound in weight was apparent when the drug stopped, but a downward BMI trend returned when they were put back on sibutramine at the close of the blind portion of the study. In comparing hypothalamic obesity to nonhypothalamic, those with HO were less responsive to the drug overall, although their change in BMI was still significant. Individuals with PWS were not separated from the group in any of the analyses, but the decrease in BMI SDS for all who were taking the drug indicates that there was a significant weight loss effect in PWS patients.

Although the study group was small, there were no significant increases in side effects for placebo compared to drug, even for those who were on SSRI drugs during the study period. This is encouraging in light of a previous report in which sibutramine withdrawal may have precipitated a psychotic episode [see Soni 2007 ]. Neurotransmitter alterations in PWS are potentially problematic for the evaluation and use of other new drugs in development for obesity; the endocannabinoid receptor blocker Rimonabant is currently under close scrutiny for use in the general population due to the potential for adverse psychiatric reactions [see recent review,
Christensen 2007 ].

So, is this the drug we've been waiting for in PWS? Maybe not. The total weight loss was good (averaging about one BMI unit; weight loss in the general obese population averages about 10 lbs), but not great. Also, it requires long term, continuous administration of the drug and it’s not clear how safe that will be. Interactions with other drugs, particularly SSRIs, remain a concern and will require careful monitoring. Nevertheless, some important points were made in this paper. First, obesity resulting from PWS can be positively impacted by drugs developed for the general obese population. Second, obesity drugs can be well tolerated by those with PWS, provided medical personnel knowledgeable about the syndrome are closely involved.

It would be of interest to determine the mechanisms of weight loss in the PWS population - were subjects less hungry between meals? Were they more easily satiated at mealtime? Were they more inclined to eat less calorie dense food? Were they obsessive about food?, etc. Much remains to be done, but this is a nice start. Many thanks to Dr. Marcus and colleagues for having the dedication to address obesity in these difficult populations, ones who are often overlooked and who stand to gain so much from effective therapy.

Topics: Research

Theresa Strong

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Theresa V. Strong, Ph.D., received a B.S. from Rutgers University and a Ph.D. in Medical Genetics from the University of Alabama at Birmingham (UAB). After postdoctoral studies with Dr. Francis Collins at the University of Michigan, she joined the UAB faculty, leading a research lab focused on gene therapy for cancer and directing UAB’s Vector Production Facility. Theresa is one of the founding members of FPWR and has directed FPWR’s grant program since its inception. In 2016, she transitioned to a full-time position as Director of Research Programs at FPWR. She remains an Adjunct Professor in the Department of Genetics at UAB. She and her husband Jim have four children, including a son with PWS.

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