DCCR Approach Reduced Appetite in PWS Patients and Animal Obesity Studies

DCCR Approach Reduced Appetite in PWS Patients and Animal Obesity Studies
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The approach used by diazoxide choline controlled-release (DCCR), Soleno Therapeutics’ investigational oral therapy to reduce appetite in people with Prader-Willi syndrome (PWS), has shown promise in improving insulin sensitivity and reducing body fat in several animal models of obesity linked to excessive eating.

The findings were reported in the review study, “The Potential Role of Activating the ATP-Sensitive Potassium Channel in the Treatment of Hyperphagic Obesity,” published in the journal Genes.

DCCR is an oral, extended-release salt form of diazoxide that works by preventing the release of neuropeptide Y (NPY) and agouti-related protein (AgRP) — two molecules thought to induce excessive appetite (hyperphagia) in patients with PWS and other forms of hyperphagic obesity.

The medication does so by activating (keeping open) ATP-sensitive potassium (KATP) channels found on nerve cells that normally release NPY and AgRP. By promoting these channels’ activities, DCCR ensures that the main mechanism used by several hormones that control appetite — including leptin, insulin and alpha-melanocortin stimulating hormone— remains functional.

The recently published review has shown that by keeping KATP channels open, DCCR can reduce appetite, body fat and liver fat, as well as improve satiety (feeling full) and insulin sensitivity in animal models of PWS, other forms of hyperphagic obesity, genetic obesity (LEPR deficiency), hyperinsulinemia (excess insulin), and diabetes.

Insulin sensitivity refers to how sensitive cells are to insulin. High insulin sensitivity allows cells to respond better to the hormone and to regulate blood sugar (glucose) levels more effectively.

“Given this range of relevant therapeutic responses that follow from activating the KATP channel, pharmacological activators of the channel could be a useful treatment option in syndromic hyperphagic obesity and may have utility in delaying the progression of these conditions,” the researchers wrote.

Similar responses also were observed in people with PWS participating in a Phase 1/2 clinical trial (NCT02034071). Results demonstrated that when administered at 1.5 mg/kg to 5.1 mg/kg, DCCR reduced excessive appetite, as well as aggressive and self-harming behaviors in these patients.

The therapy now is being tested in a Phase 3 trial (NCT03440814), called DESTINY PWS, which earlier this year completed its target enrollment of 100 participants. Top-line data are expected soon.

“We have completed enrollment in our ongoing Phase 3 clinical trial, DESTINY PWS, evaluating DCCR in PWS patients, and remain on track to announce top-line data during the current quarter,” Anish Bhatnagar, MD, CEO of Soleno Therapeutics, said in a press release.

The 13-week study is designed to evaluate the effects of once-daily treatment with DCCR, at a dose of 75–450 mg, compared to a placebo.

The main goal of the study is to assess changes in hyperphagia (measured with a questionnaire) from baseline to week 13.

Secondary goals include assessing changes in patients’ body fat, and in clinical progress evaluations by clinicians and caregivers.

After completing DESTINY PWS, patients will have the opportunity to enroll in the C602 study (NCT03714373, and still recruiting), in which all participants will continue treatment with DCCR for up to three years.

DCCR previously received orphan drug designation for the treatment of PWS in the U.S. and the European Union, as well as fast track status by the U.S. Food and Drug Administration in 2018.

Joana holds a BSc in Biology, a MSc in Evolutionary and Developmental Biology and a PhD in Biomedical Sciences from Universidade de Lisboa, Portugal. Her work has been focused on the impact of non-canonical Wnt signaling in the collective behavior of endothelial cells — cells that made up the lining of blood vessels — found in the umbilical cord of newborns.
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José holds a PhD in Neuroscience from Universidade of Porto, in Portugal. He has also studied Biochemistry at Universidade do Porto and was a postdoctoral associate at Weill Cornell Medicine, in New York, and at The University of Western Ontario in London, Ontario, Canada. His work has ranged from the association of central cardiovascular and pain control to the neurobiological basis of hypertension, and the molecular pathways driving Alzheimer’s disease.

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Joana holds a BSc in Biology, a MSc in Evolutionary and Developmental Biology and a PhD in Biomedical Sciences from Universidade de Lisboa, Portugal. Her work has been focused on the impact of non-canonical Wnt signaling in the collective behavior of endothelial cells — cells that made up the lining of blood vessels — found in the umbilical cord of newborns.
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