Results of Beloranib Clinical Trial In PWS Published

The results of Zafgen's phase 3 study evaluating the use of the drug beloranib to curb hunger and induce weight loss in individuals with PWS has been published. The study was conducted by McCandless, et al; an abstract is here

Those familiar with this clinical trial will recall that the study was prematurely halted because of safety issues – two individuals who were taking the drug died unexpectedly of blood clots in their lungs (pulmonary embolism). These tragic deaths occurred well into the study, and thus the company was able to analyze the data that had been collected to that point, to gain an understanding of whether the drug was able to reduce hunger and cause weight loss in PWS.

The study found that participants who received beloranib had decreased hyperphagia, and they experienced weight loss. 

Beloranib Outside of the PWS Context

Prior to being used in patients with PWS, beloranib had been tested in otherwise healthy obese individuals. It worked very well in those individuals, with reported reductions in hunger and significant weight loss. But, because several other weight loss drugs that have had an effect in typical populations don’t seem to have any effect in PWS, it wasn’t clear if beloranib would work in PWS. A small (17 participants), short term (8 weeks), Phase 2 study of beloranib in PWS had shown some encouraging signs, and this Phase 3 study was designed to be a “pivotal” trial – one that Zafgen hoped would show convincingly that beloranib could curb hunger and decrease weight in PWS, without any major safety issues.

Beloranib Clinical Trial In PWS 

The study (NCT02179151) was a placebo-controlled study in which participants were assigned randomly to either placebo, or beloranib at low (1.8mg) or higher (2.4 mg) dose. Participants received the same dose twice weekly for 26 weeks, and then could elect to participate in an “open label extension”, where they could choose to receive the 2.4 mg dose of beloranib for another 26 weeks. To see if the drug worked to reduce hunger, the ‘hyperphagia questionnaire for clinical trials’ (HQ-CT) was used to measure the severity of hyperphagia (excessive, unrelenting hunger). Weight was monitored, along with fat and muscle mass, and behavior and quality of life. The safety of the drug was also assessed.

In all, 107 individuals with PWS (age 12 & up) participated in the study. The paper reports on the first portion of the study (the 26 week, placebo-controlled segment), and the results were significant. Compared to those receiving placebo, participants who received beloranib at 1.8 mg/day and 2.4 mg/day had decreased hyperphagia scores on the HQ-CT questionnaire and experienced weight loss. While those who received placebo injections had, on average, a gradual increase in weight (+4%) over the course of the 26 weeks, those receiving 1.8 mg of beloranib dropped an average of ~8% of their weight and those receiving 2.4 mg/day dropped an average of 9.5% of their weight. More than 35% of those on the lower dose and 51% of those on the higher dose showed significant weight loss, while no individuals on placebo had similar weight loss. Importantly, the vast majority of weight loss was accounted for by a loss of body fat, rather than muscle, and metabolic parameters (e.g., cholesterol levels) improved as well. For the group of PWS patients receiving receiving the drug, all aspects of hyperphagia measured (eg, asking for food, actively seeking food, getting upset about food) showed overall improvements compared to the placebo group.

Note that there was some individual variability in the effectiveness of the drug - while the majority of those receiving beloranib experienced weight loss and/or improvements in hyperphagia, there were a few individuals on the drug who showed slightly increased weight or slightly worsening hyperphagia scores. Nonetheless, the overall picture was one of significantly improved hyperphagia, and significant weight loss driven by loss of fat for the group receiving beloranib.

Understanding Impact and Mechanisms

One question that is not completely resolved in this study, and which will continue to be a point of discussion for other studies addressing hyperphagia in PWS, is what level of reduction in hyperphagia score is “clinically meaningful’. In other words, how much does hunger need to be reduced to have an important impact on health and quality of life? Here, the authors show that an average reduction of 7.7 points on the HQ-CT scale was associated with caregivers reporting that food-related behavior was ‘moderately’ or ‘much’ better, suggesting that this may be a reasonable threshold. There likely is room for additional discussion and refinement around this issue as clinical trials of hyperphagia in PWS progress - these assessments are challenging to interpret and apply to understanding the drug’s impact on everyday living. Nonetheless, it is clear from this study that beloranib did result in meaningful reductions in food-related problems for the majority of individuals receiving it.

So, while the deaths that resulted from beloranib treatment clearly make the drug unacceptable for further use in the PWS population at this point, and the company ceased its development, the results do demonstrate that hyperphagia in PWS can be treated with a drug. This is a critical point, and something that had not been demonstrated previously, and it suggests that a better understanding of how beloranib works to reduce hunger might guide the development of new drugs, targeting the same pathway but without the same problems with blot clotting.

To this end, exactly how beloranib works to reduce hunger and decrease fat mass is not completely understood at this time, but there is ongoing research in this area. The drug is a ‘methionine aminopeptidase 2 (MetAP2) inhibitor’, meaning it interferes with a normal process in which some proteins are modified to remove the very first amino acid after they are made. Another recently published paper by a group at Seattle Children’s Research Institute, headed by Christian Roth, sheds some light on the pathways activated when beloranib is administered, and those that likely are not involved.

In the study (Elfers et al: ), two types of obese rats (one due to a defect in the hypothalamus, the other due to a genetic ‘knock out’ of a gene important in weight control, MC4R) were given beloranib for 12 days. The drug caused both types of animals to eat ~30% less food and lose weight. Body temperature and physical activity were not different after beloranib treatment, suggesting that these mechanisms don’t play a role in beloranib-induced weight loss. The authors studied the neurochemical changes in the brain after beloranib administration and found a neurochemical known to be important in controlling food intake (alpha-MSH) increased markedly in the rats with the hypothalamic defect. This change may cause the obese rats to become more sensitive to the hormone leptin, which normally functions to reduce food intake. The rats also showed reduced levels of markers of inflammation, which are common in obesity.

Conclusions Of PWS Clinical Trial 

The authors conclude that beloranib causes a reduction in food intake through effects on brain circuits that drive food intake. Although a strong start in defining beloranib’s mechanism of action, additional studies will be needed to completely define how beloranib works, and to capitalize fully on the information for future drug development.


For now, the evaluation of beloranib in PWS has been halted, given the deaths that occurred in the study, and the drug is no longer in development. However, Zafgen is working on the ‘next generation’ of MetAP2 inhibitors, which target the same pathway to reduce hunger but may not have the same problem with respect to blood clotting. A ‘second generation’ MetAP2 inhibitor is currently being tested in small studies of ‘normal’ (non-PWS) obesity.

Finally, this study is a reminder that there are unknown risks when testing experimental drugs. Our hearts are broken for the families who lost their loved ones during this study. We also know that, as things stand today, far too many young lives are lost because PWS hunger cannot be effectively controlled. Thus, the risk of new drugs must be weighed against the tremendous need – and this is not a simple issue. But, this study does suggest that it is possible reduce hunger and induce weight loss in those with PWS, and that is a reason to be hopeful.

For updated information on PWS clinical trial opportunities and to sign up for a monthly PWS Clinical Trial Alert, visit our PWS Clinical Trials page

PWS Clinical Trials

Topics: Research

Theresa Strong


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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