▎Editor of WuXi AppTec content team

Today, Pfizer announced the results
of two new clinical trials of the oral GLP-1 agonists danuglipron and PF-07081532.

The results of the trial showed that both oral GLP-1 agonists began to significantly reduce the patient's weight and blood glucose within a few weeks of taking it
.

Pfizer says the two therapies have the potential to become potential
"best-in-class" oral GLP-1 receptor agonists.

Obesity and type 2 diabetes represent an unfinished medical need worldwide
.

It is estimated that by 2030, the number of obese people worldwide will reach 1.
12 billion, and the number of people with type 2 diabetes will reach 643 million
.

Obesity significantly increases the risk of multiple comorbidities, including more than 200 chronic diseases
.

Glucagon-like peptide 1 (GLP-1) is a polypeptide hormone secreted by intestinal cells that stimulates the secretion of insulin by binding to GLP-1 receptors and inhibits the secretion of glucagon, thereby promoting glucose metabolism
.

At the same time, it can also play a role
in delaying gastric emptying and suppressing appetite.

Therefore, it is a powerful target for the treatment of obesity and type 2 diabetes
.

At present, a number of GLP-1 analogues have been approved for marketing, and they continue to extend the half-life
of GLP-1 analogues through the modification of polypeptide structures.

Novo Nordisk's semaglutide, for example, has an extended half-life of 165 hours, and it was approved by the FDA at the end of 2017 as a weekly GLP-1 receptor agonist
.

However, these drugs require patients to receive injections, and patients prefer convenient oral drugs
.

In 2019, Novo Nordisk's oral smeglutide was approved for marketing by the FDA, becoming an important milestone
in the development of oral GLP-1 receptor agonists.

This formula combines smeglutide with absorption enhancers to promote peptide absorption while preventing them from being degraded
by peptidase enzymes in the stomach.

However, it still needs to be taken at a specific time to maintain an effective absorption dose
.

The Evolving Evolution of GLP-1 Receptor Agonists (Image source: Reference [2])

The danuglipron and PF-07081532 developed by Pfizer are two small molecule GLP-1 receptor agonists, and unlike the macromolecule GLP-1 analogue, they are easier to take and are not limited
by food or time.

PF-07081532, optimized on a danuglipron basis, has a longer half-life and supports once-daily oral use
.

Today Pfizer announced the results
of a Phase 1b clinical trial of PF-07081532 in patients with type 2 diabetes and obesity.

At the same time, in patients with type 2 diabetes and obesity, PF-07081532 dose-dependent reduces the weight
of patients.

Patients treated with the highest dose lost an average of about 10 kg
of body weight after 4-6 weeks of treatment.

▲PF-07081532 dose-dependent type reduces patient weight (Source: Pfizer official website)

The trial results released today also include the results of a 16-week phase 2b clinical trial of danuglipron in the treatment of patients with type 2 diabetes
.

The results of the trial showed that after 16 weeks of treatment, the levels of glycosylated hemoglobin (HbA1c) were significantly reduced
in all dose groups compared with placebo.

In the highest two dose groups (80 mg twice daily and 120 mg twice daily), HbA1c levels were reduced by 0.
96 and 1.
18 percentage points
compared to baseline.

▲ Danuglipron significantly reduced HbA1c levels (Source: Pfizer)

In terms of reducing the weight of patients, danuglipron also achieved good results, the weight of patients in the highest two dose groups was significantly reduced after 16 weeks compared with placebo, and the average weight reduction in the highest dose group was close to 10 pounds, and did not reach the plateau period
.

▲ Danuglipron significantly reduced the weight of patients (Source: Pfizer official website)

In terms of safety, the tolerance and safety of both drugs are similar to those of existing GLP-1 agonists, with the main adverse events being mild and the most common adverse events being gastrointestinal reactions, including nausea, diarrhea, and vomiting
.

Based on these positive results, Pfizer plans to conduct a Phase 2b clinical trial to further evaluate the efficacy and safety of two oral GLP-1 agonists, and based on the combined results, select an investigational drug to enter Phase 3 clinical trials
.

From the first GLP-1 agonist drug to FDA approval to oral smeglutide on the market
.

GLP-1 agonists have gone through several iterations, and now advances in small-molecule oral GLP-1 agonists are expected to bring more effective and convenient treatments for patients with type 2 diabetes and obesity
.

We look forward to the joint efforts of members of the pharmaceutical ecosystem to bring more and better therapies
to the majority of patients.
"

[1] Analyst and Investor Call to Review Oral GLP-1 Data.
Retrieved September 21, 2022, from https://s28.
q4cdn.
com/781576035/files/doc_presentation/2022/09/2022-EASD-IR_Presentation_FINAL.
pdf [2] Nauck et al.
, (2021).
Another milestone in the evolution of GLP-1-based diabetes therapies.
Nature Medicine, doi:10.
1038/s41591-021-01394-7Disclaimer: WuXi AppTec content team focuses on the progress of
biomedical health research worldwide.

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.

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.