Dapiglutide in Clinical Trials: A Promising Dual GLP-1R/GLP-2R Agonist for Obesity Treatment

What is Dapiglutide?

Dapiglutide (also known as ZP7570) is a novel medication being developed for the treatment of obesity and overweight. It belongs to a class of medications called dual receptor agonists, specifically targeting two important hormone receptors in the body1. What makes dapiglutide unique is that it works on both Glucagon-like peptide-1 receptor (GLP-1R) and Glucagon-like peptide-2 receptor (GLP-2R) simultaneously2.

This dual-action approach is relatively new in the field of weight management medications. Most currently available medications for obesity target only one pathway or receptor, but dapiglutide's ability to influence two related but distinct systems in the body may offer advantages in terms of effectiveness and possibly addressing multiple aspects of obesity1.

How Does Dapiglutide Work?

Dapiglutide works through a mechanism called GLP-1/GLP-2 receptor agonism1. Let's break down what this means:

• GLP-1 receptor agonism: GLP-1 (Glucagon-like peptide-1) is a hormone naturally produced in your intestines that helps regulate blood sugar levels, slows stomach emptying, reduces appetite, and can promote weight loss. By activating GLP-1 receptors, dapiglutide mimics and enhances these effects.
• GLP-2 receptor agonism: GLP-2 (Glucagon-like peptide-2) is another hormone that plays roles in intestinal health, nutrient absorption, and gut barrier function. By targeting GLP-2 receptors, dapiglutide may help improve gut health and potentially reduce inflammation.

This dual-targeting approach is what distinguishes dapiglutide from single-target medications like some other weight loss drugs. The combination of reduced appetite, slower digestion, and potentially improved gut health may contribute to its effectiveness in weight management12.

Conditions Treated with Dapiglutide

Based on the clinical trials information, dapiglutide is being developed primarily for the following conditions:

• Obesity: The medication is being studied in people with a Body Mass Index (BMI) of 30 kg/m² or higher1.
• Overweight: Some trials are including participants with a BMI of 27 kg/m² or higher2.
• Inflammation: The medication may also have effects on inflammation, as suggested by some of the trial outcomes measuring inflammatory markers1.

The clinical trials are specifically looking at how dapiglutide might affect not only body weight but also related health markers such as liver health indicators, blood pressure, heart rate, and inflammation levels. This suggests the medication might have broader health benefits beyond just weight reduction1.

How Dapiglutide is Administered

Dapiglutide is administered as a subcutaneous injection, which means it's injected just under the skin. Based on the clinical trial information, the key aspects of its administration include:

• Injection site: The injections are given in the abdomen (stomach area)1.
• Frequency: The medication is administered once weekly in the studied treatment protocols1.
• Dosing: Various doses are being studied:
  • In the DREAM trial, doses of 4 mg and 6 mg are being tested1.
  • Another study is testing a single 7.5 mg dose in different concentrations (10 mg/mL and 25 mg/mL)2.
• Titration: The dose is gradually increased to minimize side effects. For example, in the DREAM trial, participants start at 2 mg weekly and then the dose is increased by 2 mg every three weeks until reaching the target dose of 4 mg or 6 mg1.
• Self-administration: Patients in the clinical trials are taught to give themselves the injections1.

The different concentrations being tested (10 mg/mL vs. 25 mg/mL) suggest that researchers are working to optimize how the medication is delivered, possibly to improve convenience or comfort for patients2.

Effectiveness of Dapiglutide

While the full results of the clinical trials are not provided in the available information, we can see what outcomes the researchers are measuring to determine effectiveness:

Primary outcomes being measured include:

• Percentage change in body weight from baseline to the end of treatment (12 weeks in the DREAM trial)1.
• Pharmacokinetic measures (how the drug moves through the body) in other trials2.

Secondary and other outcomes include:

• Significant weight loss thresholds: Proportion of participants achieving weight loss of ≥5%, ≥10%, and ≥15%1.
• Changes in BMI (Body Mass Index)1.
• Changes in blood pressure (both systolic and diastolic)1.
• Changes in resting heart rate1.
• Changes in body composition as measured by bioimpedance (a method of estimating body fat and muscle mass)1.
• Liver health indicators, including measures of liver steatosis (fat in the liver) and fibrosis (scarring)1.
• Inflammation markers in the blood, such as high-sensitivity C-reactive protein (hs-CRP) and interleukin-6 (IL-6)1.
• Gut permeability biomarker (LPS-binding protein), which may indicate how well the intestinal barrier is functioning1.
• Quality of life measures, including the 36-Item Short Form Survey and the IWQOL-Lite-CT (Impact of Weight on Quality of Life questionnaire)1.

These comprehensive measures suggest that researchers are evaluating not just the weight loss potential of dapiglutide but also its broader health effects and impact on patients' wellbeing1.

Current Clinical Research

Based on the available information, dapiglutide is currently being studied in clinical trials, including:

• The DREAM trial (Dapiglutide for the Treatment of Obesity): This is a randomized, double-blind, placebo-controlled, proof-of-concept study. It involves 54 participants with obesity (BMI ≥30 kg/m²) who are randomized to receive dapiglutide 4 mg, dapiglutide 6 mg, or placebo for 12 weeks1.
• Pharmacokinetic study: This is an open-label, randomized, parallel-group study comparing two different concentrations of dapiglutide (10 mg/mL and 25 mg/mL) after a single dose of 7.5 mg in participants with overweight or obesity (BMI ≥27.0 kg/m²)2.

The DREAM trial includes a gastroduodenoscopy sub-study in which some participants undergo procedures to obtain gastric and duodenal (small intestine) biopsies before and after treatment. This suggests researchers are investigating how the medication affects the digestive tract at the tissue level1.

These studies represent early-phase clinical research (Phase 1 for the pharmacokinetic study), indicating that dapiglutide is still in the developmental stages and not yet approved for general use12.

Safety Profile and Side Effects

The available information doesn't provide a comprehensive list of observed side effects, but we can gain some insights from the trial designs:

• Safety monitoring: Both trials include monitoring for adverse events (side effects) as part of their outcomes12.
• Dose titration: The gradual increase in dose (starting at 2 mg and increasing by 2 mg every three weeks) suggests that starting with higher doses might cause more side effects, which is common with GLP-1 receptor agonists1.
• Tolerability considerations: The DREAM trial protocol mentions that "To reduce dropout in cases of low tolerability of the IMP, the investigator can postpone up-titration or down-titrate if judged necessary for participant retention or safety." This indicates that researchers anticipate some participants might experience side effects that could affect their ability to tolerate higher doses1.

Based on other medications in the GLP-1 receptor agonist class, potential side effects might include nausea, vomiting, diarrhea, constipation, and abdominal pain. However, the specific side effect profile of dapiglutide, particularly with its dual GLP-1/GLP-2 receptor action, will become clearer as more clinical trial results are published12.