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A first-in-class antisense oligonucleotide — RES-010 (Resalis Therapeutics, Turin, Italy) — may complement and enhance the efficacy of antiobesity drugs such as GLP-1 receptor agonists (RAs), preclinical experiments and an ongoing phase 1 trial suggested.

The treatment acts upstream at the gene regulatory level by targeting miR-22, a master regulator of lipid metabolism, mitochondrial function, and adipose tissue remodeling. RES-010 simultaneously modulates multiple interconnected pathways, with the aim of reprogramming “metabolic homeostasis,” according to Resalis.

By targeting the miR-22 pathway, “RES-010 is designed to selectively reduce fat while preserving muscle mass,” potentially improving the effectiveness of current obesity treatments, said Almut Nitsche, PhD, Resalis’ chief medical and development officer, in a statement.

The ongoing trial “is an essential step toward translating our preclinical insights into clinical advancements,” noted Nitsche, who presented the findings at the European Association for the Study of Diabetes (EASD) 2025 Annual Meeting in Vienna, Austria.

‘Sustained Weight Loss’ Preclinically

RES-010 was evaluated in murine models of obesity to assess its effects on body weight and metabolic health. It was also studied in nonhuman primates subjected to a fast-food diet and in a three-dimensional model of human primary adipose tissue to evaluate its impact in translationally relevant settings. The combination of RES-010 with a GLP-1 RA also was investigated in murine models to assess potential additive or synergistic effects.

In obese mice, the treatment led to a significant and sustained weight loss, with effects persisting after treatment discontinuation. In combination with a GLP-1 RA, RES-010 potentiated weight loss, enabling a less intensive semaglutide treatment regimen while maintaining efficacy.

In nonhuman primates on a fast-food diet, use of RES-010 showed a reduction of body weight in animals with unhealthy adiposity. Overall, the preclinical studies demonstrated a favorable safety and tolerability profile, with no significant adverse effects.

The phase 1 double-blind, randomized, placebo-controlled, dose-escalation trial was launched in November 2024 in the Netherlands to assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of RES-010 in healthy volunteers and those with overweight or moderate obesity.

The study consists of two parts: a single ascending dose (SAD) phase and a multiple ascending dose (MAD) phase.

In the SAD phase, healthy male and female participants receive incremental single doses of RES-010 to evaluate safety and pharmacokinetics. In the subsequent MAD phase, patients with overweight and moderate obesity receive multiple doses to further assess the treatment’s safety and tolerability.

Exploratory endpoints include assessing the effect of RES-010 on specific metabolic markers, changes in lipid metabolism, body weight, appetite, and glucose tolerance.

Data from the combined SAD/MAD study, which involves multiple phases of dose escalation and safety evaluation, are expected by mid-2026.

Molecular Mechanisms Unclear

“Without a full peer-reviewed paper, it is difficult to comment on the study,” Adam Collins, associate professor of nutrition at the University of Surrey, Guildford, England, said in a related commentary.

“However, I would be wary of claims of ‘reprogramming metabolism.’ Mechanistically, this is speculative; without knowing the direct effects this is having on adipose tissue (fat cells) storage and mitochondrial function (eg, fat burning and thermogenesis),” he said. “Even then, the exact molecular mechanisms behind these effects remain unclear.”

“It is essential to see the full paper…before interpreting any overall weight loss results,” he concluded.

Nitsche declared having no competing interests. Collins did not provide information on competing interests.

Marilynn Larkin, MA, is an award-winning medical writer and editor whose work has appeared in numerous publications, including Medscape Medical News and its sister publication MDedge, The Lancet (where she was a contributing editor), and Reuters Health.