Weekly Setmelanotide Still as Safe and Effective as Daily Formulation, Trial Data Suggests

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by Joana Carvalho |

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Rhythm, Setmelanotide

The new weekly formulation of setmelanotide, Rhythm Pharmaceuticals’ lead candidate for rare genetic obesity disorders, continues to be as effective and safe at promoting weight loss in healthy obese individuals as its daily formulation, according to new interim data from a Phase 2 clinical trial.

The findings, which build on previous data, were presented recently by Gregory Gordon, MD, vice president of Clinical at Rhythm, in an oral presentation, “A Randomized Trial of a Once-Weekly Formulation of Setmelanotide in Individuals with Obesity,” at the 2020 ObesityWeek, held virtually, Nov. 2–6.

In addition to those findings, Rhythm also presented new data from an ongoing long-term extension study (NCT03651765) showing that setmelanotide enabled patients with POMC deficiency to control their hunger and continue losing weight for up to three years.

“We are excited to share new data from across our setmelanotide development program that support its potential as a new medicine for people with rare genetic disorders of obesity,” Murray Stewart, MD, chief medical officer of Rhythm, said in a press release.

Setmelanotide works by activating the melanocortin-4 receptor (MC4R), a protein receptor that is part of a signaling cascade that controls hunger and satiety (feeling full).

By activating the MC4R signaling pathway, which is impaired in several genetic obesity disorders including POMC deficiency and LEPR deficiency, setmelanotide is expected to help these patients regain control of their appetite and to lose weight.

The U.S. Food and Drug Administration (FDA) is reviewing an application from Rhythm requesting the approval of setmelanotide’s daily subcutaneous (under-the-skin) formulation for the treatment of those with POMC and LEPR deficiencies. A decision is expected by Nov. 27.

Meanwhile, the company started developing a new weekly formulation of setmelanotide based on Camurus’ extended-release FluidCrystal injection depot technology, which Rhythm licensed for setmelanotide in 2016.

“As we prepare for a potential FDA approval in proopiomelanocortin (POMC) and leptin receptor (LEPR) deficiency obesities later this month, we are focused on ongoing efforts to fundamentally alter the treatment paradigm for rare genetic disorders of obesity and continue advancing weekly setmelanotide as a potential option that may be more convenient and less burdensome for patients and their families,” Stewart said.

In June, Rhythm presented early data from a Phase 2 trial designed to assess the safety, tolerability, effectiveness, and pharmacological properties of the therapy’s new weekly formulation in healthy obese individuals.

Following enrollment, study participants were assigned randomly to receive setmelanotide once weekly (10, 20, or 30 mg, with or without titration), once daily — 2 mg in the first week, and 3 mg thereafter — or a placebo, for a total of 12 weeks.

A preliminary analysis involving 75 patients revealed that both treatment regimens were safe and well-tolerated. Also, the pharmacological properties of both setmelanotide formulations were identical, as was their effectiveness at promoting weight loss.

Rhythm now announced updated findings from the trial, which included data from 85 participants gathered until April 17.

Analyses indicated that, as of the cut-off date, both setmelanotide formulations continued to be safe and well-tolerated, and to show a safety profile consistent with previous reports.

The incidence of treatment-emergent adverse events (side effects) also was similar between the two therapy formulations. The most common adverse events observed in both groups included injection site reactions, skin darkening, nausea, headache, and vomiting.

Consistent with earlier reports, the two formulations had similar effectiveness at helping patients control their hunger and lose weight over the 12-week treatment period, compared with a placebo.

“These data demonstrate that the weight and hunger score changes with the weekly formulation were generally comparable to the daily formulation,” Gordon said.

“It is worth noting that the changes with both formulations in normal obese individuals were smaller relative to data we’ve reported separately in patients with rare genetic obesities associated with an impaired MC4R pathway,” Gordon added. “This reinforces the important role the MC4R pathway plays in regulating hunger, caloric intake, and energy expenditure and the potential for a precision medicine treatment approach in certain patients with severe obesity.”

Pharmacological analyses also showed that the levels of setmelanotide in the participants’ bloodstream were identical throughout the entire treatment period in both formulations. When given once weekly, setmelanotide’s levels remained stable for an entire week, with concentrations falling within the range previously determined to be effective for the daily formulation.

In addition to these findings, Rhythm also presented two additional posters on the effects of setmelanotide in people with POMC and LEPR deficiencies.

In the poster “Long-term Weight and Hunger Reduction With Setmelanotide in Individuals With POMC Deficiency Obesity,” Karine Clément, MD, PhD,  presented the latest findings from an extension study that is assessing the long-term safety and tolerability of setmelanotide in patients with POMC and LEPR deficiencies. Clément is professor of Nutrition at Pitié-Salpêtrière Hospital and Sorbonne Université, in Paris.

This analysis focused on the nine POMC patients who enrolled in the study so far, all of whom had completed one year of treatment with setmelanotide in a previous Phase 3 trial (NCT02896192).

As of April 16, five of these patients already had completed 89 weeks (more than one-and-a-half years) of treatment with setmelanotide in the extension study.

Since starting treatment with setmelanotide in the original trial, up until week 89 of the extension study, patients had lost a total of 40.2 kg (88.6 pounds), their body mass index dropped by 32.5%, and their hunger scores dropped by 8.2%. Over the course of the extension study, body weight reduced by 0.5 kg (1.1 pounds), BMI by 0.4%, and hunger scores by 10%.

As reported earlier, the findings demonstrated that patients were able to maintain control of their hunger and continue losing weight while receiving treatment for up to three years.

Setmelanotide also was well-tolerated in the extension study, with a safety profile consistent with prior reports. The most common side effects observed to date included injection site reactions, nausea, vomiting, and skin darkening.

In the second poster, “Suicidality and Depression in Individuals With Genetic Obesity Treated With Setmelanotide,” Peter Kühnen, MD, presented an analysis of two previously completed Phase 3 trials of setmelanotide that assessed the effects of treatment on patients’ depression and suicidal thoughts. Kühnen is with the Institute for Experimental Pediatric Endocrinology at Charité Universitätsmedizin in Berlin.

The analysis, which was based on data from 10 patients with POMC/PCSK1 deficiency and 11 with LEPR deficiency who enrolled in one of the two studies (NCT02896192 or NCT03287960), revealed that setmelanotide was well-tolerated and not associated with increased levels of depression or suicidal thoughts in any of the trials.

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