Saniona announced that adolescents with Prader-Willi syndrome (PWS) showed improvements in weight, body mass index (BMI), and hyperphagia score — measuring appetite reduction — when treated with the investigational therapy Tesomet in a 24-week, open-label extension of a Phase 2a clinical trial.
Tesomet is a combination of two medications — tesofensine and metoprolol. The first, tesofensine, prevents the reuptake of serotonin, norepinephrine, and dopamine — three main signaling molecules that regulate brain activity. Increasing the amounts of these neurotransmitters outside brain cells can reduce appetite. As such, treatment with tesofensine is associated with weight loss and liver fat reduction.
Despite its positive therapeutic effects, however, tesofensine can cause an abnormal heart rate. Metoprolol is a beta-blocker that can manage the abnormal heart rate and resolve this problem.
In the first part of this study — initial results reported in 2018 — six adults with PWS were treated daily for three months with Tesomet (0.5 mg of tesofensine and 50 mg of metoprolol), while three other patients received a placebo formulation. Results showed that those treated with Tesomet had clinically meaningful weight loss, and a reduction in excessive eating (hyperphagia).
However, at the time, researchers pointed out that the results must be interpreted with caution as only four of the patients completed the trial — two in the Tesomet group, and two in the placebo group. Further, the data suggested that patients could potentially benefit from a lower dose of the medication.
The second part of the study was a three-month, double-blind trial with adolescent PWS patients, followed by two open-label extension studies, each of three-month duration.
In the double-blind phase, five adolescents with PWS received a lower daily dose of 0.125 mg/day Tesomet (tesofensine 0.125 mg plus metoprolol 25 mg), while four received a placebo formulation. During the first open-label extension phase, eight of the nine participants continued to receive 0.125 mg/day Tesomet for an additional three months.
However, despite finding that the lower dose was safe and well-tolerated, it failed to produce the plasma levels observed earlier with the 0.5 mg daily dose. Thus, researchers adjusted the dose regimen on the second open-label extension phase to 0.25 mg daily for three months.
This second extension phase began with four of the eight adolescents with PWS. One patient dropped out after two months due to a non-drug-related infection.
The higher 0.25 mg/day dose of Tesomet had a positive effect on body weight and BMI in all three remaining adolescents with PWS, compared with the placebo and with the 0.125 mg/day dose. During the three-month period, the average body weight of the three patients decreased by 2.6%, and their average BMI measurements decreased 4.0%.
In comparison, during the first three-month double-blind study at the lower 0.125 mg/day dose, the patients’ average body weight increased by 2.2%, and their BMI values increased 1.7%. An average weight gain of 2.3%, and an increase in BMI of 0.8%, also was reported during the first extension period at the lower dose.
Additionally, the hyperphagia scores — based on a questionnaire given to the caregivers in which zero means no hyperphagia, and 36 means extreme insatiable hunger — also were reduced in PWS adolescents taking the higher dose. Their scores dropped to low single-digits.
The average baseline score for the three patients at the beginning of the study was 8.7. After the 3-month period at the higher dose (0.25 mg/day Tesomet), the average score was 2.7 — representing a reduction of 69% compared with baseline.
“The open label extension of the PWS study data confirms analyses from a previous adult study that the predicted 0.25 mg daily dose would be safe and efficacious in this patient population. Importantly, we have now treated adolescent patients with PWS for 9 months with Tesomet, and are encouraged by its safety and efficacy,” Jørgen Drejer, CEO of Saniona, said in a press release.
Based on these data, Saniona is planning to conduct Phase 2b/3 studies testing Tesomet. The company recently established a scientific advisory board to support these future trials.
“The data provide strong de-risking and guidance for the pivotal Phase 2b/3 studies that we are now planning in PWS and other rare eating disorders, including hypothalamic obesity,” Drejer said. “We are confident that Tesomet has the potential to significantly reduce weight, BMI, and treat debilitating hyperphagia in severe, rare and highly underserved eating disorders.”
The researchers noted that the small number of participants precluded any statistical evaluation. But they said the extension studies showed “signals of efficacy.”
“Weight gain, hyperphagia, and obsession with food are the greatest burden on both patients with Prader-Willi syndrome and their families,” said Dóra Török, MD, PhD, primary investigator of the Tesomet Phase 2a study.
“This novel drug appears to help controlling weight and appetite, and it decreases preoccupation with food. Therefore, patients are more available to other activities, and life as a whole becomes easier,” she added.