Setmelanotide Reduces Weight and Hunger in Patients with HET Obesity, Early Data Show

Setmelanotide Reduces Weight and Hunger in Patients with HET Obesity, Early Data Show

Setmelanotide is showing promising efficacy to reduce weight and hunger in patients with melanocortin-4 receptor (MC4R) pathway heterozygous obesity, particularly those with more severe genetic mutations, announced the treatment’s developer Rhythm Pharmaceuticals.

The findings come from updated preliminary data from Rhythm’s Phase 2 trial (NCT03013543) to evaluate setmelanotide (RM-493) for several rare genetic obesity disorders, including POMC deficiency (heterozygous or epigenetic), LEPR deficiency, Bardet-Biedl syndrome, and Alstrom syndrome.

In the study, patients receive a setmelanotide injection once daily under the skin. Efficacy is primarily measured by the medication’s effect on weight loss. Other measures include its effect on hunger, body fat mass, and insulin sensitivity, as well as its possible side effects. The study has a duration of one year.

Heterozygous (HET) obesity is caused by a mutation in one copy of a gene involved in the MC4R pathway, such as the POMC, PCSK1, or LEPR gene.

Not all patients with variations in these genes will be obese because HET obesity has variable penetrance, which means that, for some reason, the disease will manifest only in a proportion of carriers.

Rhythm believes this variability may lie with the type of variant involved. So-called higher-impact loss of function (LOF) variants may have harsher effects over the MC4R pathway, making patients who carry them more prone to severe obesity.

Based on this genetic heterogeneity, the company decided to group patients in the study into carriers of high-impact LOF and carriers of other LOF types. The rationale for this approach comes from recent clinical results that suggest setmelanotide had a greater clinical benefit for those with high-impact variants.

In the study, all four patients with this high-impact variant remained on therapy. Two of them had been treated for more than 29 weeks.

The first patient, who weighed 205 kilograms (kg) or 451 pounds (lbs) at the beginning of the study, lost 18.4 kg (40.5 lbs) and experienced a hunger score decrease of 90% after 37 weeks of treatment.

The other patient weighed 129 kg (284 lbs) and lost 22.2 kg (49 lbs), with a hunger score decrease of 71.4%, following 29 weeks of treatment.

The other two patients initiated treatment only recently but are showing promising weight loss and hunger reduction.

Patients with other LOF variants were included in the trial. From the initial nine patients, five remain on therapy, which lasted between seven and 74 weeks. The other four discontinued treatment due to lack of efficacy, side effects, or non-compliance with study protocol.

Of those who remain on treatment, one experienced a clinically-meaningful weight loss — greater than 10% — and three others had more modest weight loss. Their hunger scores also decreased, ranging from a 20% to 80% reduction, from the start of the study. One patient has been on treatment for too short a period to report a response.

Consistent with prior clinical data, setmelanotide continues to be well-tolerated, with no serious side effects reported, according to Rhythm.

“Today’s announcement marks an important milestone in our efforts to assess the full range of setmelanotide’s potential applications,” Keith Gottesdiener, MD, chief executive officer of Rhythm, said in a press release.

“(W)e have identified a wide spectrum of heterozygous LOF variants and believe there is a relationship between LOF variant and impact on pathway function. This belief is corroborated by the new clinical data announced today, as patients with high-impact LOF variants experienced a more consistent and greater response to setmelanotide.”

In addition, Rhythm will continue to evaluate setmelanotide’s potential for other patient groups, including those with partial LOF, newly-characterized or more common variants, as well as composite HET variants (meaning they have more than one gene affected).

The company is set to continue its broader development program for setmelanotide, expecting to meet several milestones throughout 2019 and 2020.

Ana is a molecular biologist enthusiastic about innovation and communication. In her role as a science writer she wishes to bring the advances in medical science and technology closer to the public, particularly to those most in need of them. Ana holds a PhD in Biomedical Sciences from the University of Lisbon, Portugal, where she focused her research on molecular biology, epigenetics and infectious diseases.
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Ana is a molecular biologist enthusiastic about innovation and communication. In her role as a science writer she wishes to bring the advances in medical science and technology closer to the public, particularly to those most in need of them. Ana holds a PhD in Biomedical Sciences from the University of Lisbon, Portugal, where she focused her research on molecular biology, epigenetics and infectious diseases.
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