Failed Alzheimer’s drug finds new life as anti-obesity pill
An experimental drug originally designed to treat Alzheimer’s has been found to reduce obesity and improve heart function in mice. The drug was previously found to be ineffective at treating dementia, but the researchers suggest it could be useful in stimulating fat metabolism.
Researchers all over the world are searching for the holy grail of anti-obesity treatments – a simple pill that can enhance the body’s ability to burn fat. A team of researchers from Johns Hopkins University has been focusing on a specific enzyme known as phosphodiesterase 9 (PDE9), one of 11 different enzymes in the phosphodiesterase superfamily.
PDE9 inhibitors have been in development for several years, although so far none have progressed all the way through clinical trials to market approval. The treatment is being explored for conditions such as sickle cell anemia and schizophrenia, but Alzheimer’s disease has probably been one of the more thoroughly researched PDE9 inhibitor targets.
One specific PDE9 inhibitor, developed by Pfizer and dubbed PF-04447943, failed to treat symptoms of Alzheimer’s disease in Phase 2 human trials. However, in 2015 Johns Hopkins researchers found the PDE9 enzyme to be highly expressed in heart tissue, suspecting it potentially contributes to heart disease.
So the next step for the research was to investigate whether PDE9 inhibitors could improve cardiometabolic abnormalities including high cholesterol, blood pressure and excess body weight. To test this, the researchers used PF-04447943 to inhibit PDE9 activity in several mouse models of obesity.
The animals were fed a high-fat diet and for up to eight weeks received either PDE9 inhibitors or a placebo. The results revealed significant weight loss was seen in some, but not all, of the mouse models. Effectiveness depended on the presence of female sex hormones.
Compared to the control, male mice on the drug dropped about 20 percent of their body weight over the study period. Importantly, this body weight drop was only in fat mass, and came with no change to physical activity or overall food consumption. An even higher drop in weight was seen in female mice with their ovaries removed – a common animal model simulating menopause.
“The finding that the experimental drug did not benefit female mice that had their ovaries shows that these sex hormones, particularly estrogen, had already achieved what inhibiting PDE9 does to stimulate fat-burning,” explains Sumita Mishra, a researcher working on the study. “Menopause reduces sex hormone levels, and their control over fat metabolism then shifts to the protein regulated by PDE9, so the drug treatment is now effective.”
The study also found a number of other cardiometabolic improvements accompanying the weight loss in mice responding positively to the drug. The drug was seen to reduce fat in the liver, lower blood cholesterol and improve a number of biomarkers associated with stresses on the heart.
Senior investigator on the study, David Kass, says if the findings translate to humans then it may be possible to drop significant volumes of body weight in a matter of weeks without any dietary or physical activity changes.
“I’m not suggesting to be a couch potato and take a pill, but I suspect that combined with diet and exercise, the effects from PDE9 inhibition may be even greater,” says Kass.
Kass points out that because the drug is currently being investigated across a number of human trials it has an already established safety profile. So it should not be difficult to swiftly mount a human clinical trial to test its anti-obesity effects.
“Currently, there isn’t a pill that has been proven effective for treating severe obesity, yet such obesity is a global health problem that increases the risk of many other diseases,” says Kass. “What makes our findings exciting is that we found an oral medication that activates fat-burning in mice to reduce obesity and fat buildup in organs like the liver and heart that contribute to disease; this is new.”
The new study was published in The Journal of Clinical Investigation.
Source: Johns Hopkins Medicine