Munich Five-Target Obesity Drug Outperforms Comparators in Mice

Each significant advance in obesity treatment has involved addressing an additional biological pathway. Researchers in Munich set out to discover what might be achieved by tackling five pathways simultaneously.

The team created one molecule capable of activating five biological targets at the same time, while overcoming a persistent issue associated with one of its added components. In mice with obesity, it performed better than every comparator medicine in the study.

One molecule, five targets

The project was headed by Professor Timo D. Müller, director of the Institute for Diabetes and Obesity at Helmholtz Munich. His researchers aimed to broaden the effects of existing gut-hormone medicines without requiring a second tablet that circulates throughout the body.

They produced a hybrid drug. One half imitates the established gut hormones GLP-1 and GIP, which reduce hunger and help stabilise blood sugar. This same pairing is already used in tirzepatide, currently the most powerful obesity injection.

Its other component is lanifibranor, a medicine that acts on proteins within cells that regulate metabolism. Activating these proteins increases a cell’s capacity to burn fat and process blood sugar.

Combined, the drug acts on two receptors located on the surface of specific cells and on three internal switches. In total, the molecule triggers five biological pathways at once.

“Our guiding question was: how can we enhance incretin activity without creating a second, systemically active source of side effects?” said Müller, the senior author.

Targeted cell delivery

Used alone, lanifibranor can improve metabolism, but it acts wherever blood circulates. This whole-body exposure created difficulties in earlier human trials, including fluid retention, anemia, and modest weight gain.

To avoid this, the Munich researchers chemically linked lanifibranor to the gut-hormone section of the molecule.

This section attaches to cells in the pancreas, gut and brain that recognise the gut hormones GLP-1 and GIP – signals that tell the brain you’re full and stabilise blood sugar. Lanifibranor enters cells only at those sites.

This targeted approach greatly lowered the amount of lanifibranor required. The dose was approximately 6,898 times lower than the standalone lanifibranor dose needed to influence liver function, which may limit unintended side effects.

Comparing obesity drugs

Mice made obese by a high-fat diet, used to model human obesity, received the hybrid for two weeks. Compared with animals given semaglutide, the active medicine in Ozempic and Wegovy, they ate less, shed more body fat and lost more weight.

The hybrid also exceeded the performance of the conventional GLP-1/GIP combination used in tirzepatide. Lanifibranor alone resulted in little weight loss, but it became much more effective when joined to the GLP-1/GIP part of the molecule.

One head-to-head human trial has found tirzepatide to be more effective than semaglutide. In this preclinical comparison, the Munich molecule outperformed both.

“The animals ate less and lost more weight than under a GLP-1/GIP co-agonist without cargo,” said Dr. Daniela Liskiewicz, co-first author and a group leader at Helmholtz Munich.

Better insulin response

The treatment reduced fasting blood sugar more than the standard GLP-1/GIP combination. In a clamp test, in which doctors administer glucose and assess how rapidly insulin removes it, the hybrid molecule clearly surpassed the comparator drug.

Part of this improvement remained after the researchers accounted for body weight. They restricted food for a separate group receiving the older medicine until its weight matched that of hybrid-treated mice. Even then, the hybrid was better at controlling blood sugar.

This indicates that the medicine may enhance insulin sensitivity independently of the amount of weight lost. When the researchers blocked PPARδ in those mice, the blood-sugar benefit vanished, while weight loss persisted.

The hybrid likewise reduced inflammation in the liver and muscle and lowered liver fat. These effects could benefit people with type 2 diabetes and fatty liver disease, which commonly occur together.

Fewer side effects

Mice given the hybrid did not show lanifibranor’s usual human-related drawbacks – fluid retention, anemia, and modest weight gain. Samples of kidney, heart, liver and muscle tissue revealed no damage.

Mice with obesity receiving the hybrid also had improved heart function compared with untreated obese controls: their hearts pumped more blood with each beat. Their blood pressure remained stable.

Healthy lean mice given the same dose experienced no reduction in weight, body fat or appetite, and their blood sugar did not fall dangerously low. The molecule seems to work chiefly in tissues affected by obesity.

From mice to humans

Before this study, nobody had put GLP-1, GIP and three PPAR switches into one molecule and tested it in a living animal.

The Munich researchers had earlier published a paper targeting three pathways at the same time. The new elements in this study are the addition of GIP and the third PPAR switch.

Should the principle translate to humans, doctors might eventually provide one weekly injection to address appetite, blood sugar, insulin response, fatty liver and inflammation. Patients could have less metabolic regain after treatment ends.

The usual limitation remains: promising animal findings frequently become weaker in human trials, and bringing this molecule to people will require years of further research.

“We see a principle with strong effects in the animal model – now the task is to optimize the approach for humans and move it towards the clinic,” said Müller. Clinical testing will require industry partners.