Pfizer Optimizes Once-Daily Oral GLP-1 Agonist Danuglipron Formulation Following Promising Phase 1 Data

On July 12, Pfizer announced that based on the pharmacokinetic results from the ongoing Phase 1 trial, the company has selected and finalized a preferred extended-release formulation for the oral GLP-1R agonist Danuglipron (PF-06882961) for once-daily dosing.

Pfizer plans to launch a dose optimization study for this sustained-release formulation in the second half of 2024 to evaluate the efficacy and safety of multiple doses, providing a reference for registrational trials.

Danuglipron (PF-06882961) is a small-molecule oral glucagon-like peptide-1 (GLP-1) receptor agonist. Unlike large-molecule GLP-1 analogs, it can be administered orally in a more convenient manner and is not restricted by food intake or timing of administration.

This ongoing Phase 1 trial is a randomized, open-label clinical trial designed to evaluate the pharmacokinetics and safety of danuglipron oral immediate-release and oral extended-release formulations in healthy adults aged 18 and above. The study results support once-daily dosing pharmacokinetic profiles, with safety consistent with previous danuglipron studies, and no elevation in liver enzymes was observed in over 1,400 study participants.

Previously, Danuglipron was administered twice daily.

In the randomized, double-blind, placebo-controlled Phase 2b clinical trial published in May last year, 411 adult patients with type 2 diabetes received different doses of danuglipron twice daily or placebo treatment. The trial results showed that 316 participants completed the treatment. After 16 weeks of treatment, compared with the placebo group, all doses of danuglipron significantly reduced patients' glycated hemoglobin (HbA1c) and fasting blood glucose levels. At 16 weeks, patients receiving 80 mg and 120 mg of danuglipron had significantly lower body weight than the placebo group, with weight reductions of 2.04 kg and 4.17 kg, respectively.

However, the incidence of gastrointestinal reactions with Danuglipron (twice daily) was high (nausea 73%, vomiting 47%, diarrhea 25%), and the discontinuation rate was also high (50%), which is why Pfizer considered developing a once-daily oral version.

Pfizer Chief Scientist and President Mikael Dolsten, M.D., Ph.D., stated: "Obesity is a key therapeutic area for Pfizer, and we have a strong pipeline, including three clinical candidates and multiple preclinical candidates. Danuglipron is the most advanced among them, with its twice-daily oral formulation already demonstrating promising efficacy. After a comprehensive analysis of prior Phase IIb data and trial design, we believe that enhancing the extended-release formulation and optimizing the trial design can advance Danuglipron, a competitive oral GLP-1 molecule, into registrational studies to address the current and ongoing medical needs of patients with obesity."

On June 26, 2023, Pfizer announced that it would stop the development of its obesity and diabetes drug Lotiglipron, which is still in the clinical trial stage. This decision was made because patients taking the drug showed elevated transaminase levels, a sign of hepatocyte damage, during the interim clinical study.

Lotiglipron belongs to a class of drugs known as glucagon-like peptide-1 (GLP-1) hormones. They mimic a GLP-1 hormone produced in the intestines, which signals the brain when a person is full. This class of GLP-1 drugs was previously used to help patients with type 2 diabetes manage their condition.

This caused Pfizer to miss the first wave of the global weight-loss drug market. During this period, Eli Lilly and Novo Nordisk took a significant lead with their injectable drugs Zepbound and Wegovy, respectively.

But Pfizer also found a problem, that is, the production cost of injectables is very high, which means limited production capacity, so the first batch of drugs can only meet the needs of a limited number of patients.

Therefore, after the failure of Lotiglipron, Pfizer focused on another oral GLP drug, Danuglipron, which was progressing more rapidly. However, by the end of 2023, clinical data showed that up to 73% of patients experienced nausea, up to 47% experienced vomiting, and up to 25% experienced diarrhea. The discontinuation rate was high across all doses. From a statistical perspective of clinical trials, a higher discontinuation rate generally indicates significant side effects that prevent patients from continuing the medication. Pfizer once announced that Danuglipron would not enter Phase 3 clinical trials.

In February 2024, Dr. Mikael Dolsten stated that Danuglipron was well-tolerated by vital organs and is a safe drug. Patients taking Danuglipron twice daily experienced an average weight loss of 6.9% to 11.7%, while those on placebo gained 1.4% at 32 weeks.

Subsequently, Pfizer abandoned the twice-daily version of Danuglipron, adjusting the dosage to once daily in an attempt to optimize the formulation for a lower dosing frequency.

Nevertheless, compared to Novo Nordisk and Eli Lilly, Pfizer still has a way to go in the weight loss field, and Danuglipron needs to provide more convincing data.

However, Pfizer's CEO is confident about this, and the information comes from two other molecules developed clinically by Pfizer. One is the oral small-molecule GLP-1 receptor agonist PF-06954522, and the other has not been disclosed due to intense competition. In addition, Pfizer is conducting numerous preclinical studies in the weight loss field.

Currently, the weight-loss drug field is becoming a bipolar multi-power situation dominated by Novo Nordisk and Eli Lilly with GLP-1 drugs, but under the huge market demand, latecomers still have opportunities.

Pfizer is also actively reshaping its competitiveness. Pfizer CEO Albert Bourla previously stated that obesity is one of the areas Pfizer is focusing on. They are advancing their own assets and are committed to making breakthroughs in the field of obesity. Meanwhile, they are still actively seeking potential licensing deals or acquiring early-stage obesity therapies.

Given that most weight-loss drugs currently on the market are injectables and face shortages, Pfizer believes that weight-loss pills could meet a huge market demand and will adopt a pricing strategy different from existing products.

Oral administration is a recognized method of drug delivery that can significantly improve adherence in patients with chronic diseases. At the same time, the development barriers of oral formulations also represent a huge opportunity, and currently, many enterprises both in and outside China are actively promoting the development of oral GLP-1 drugs.

First is Novo Nordisk's oral semaglutide (Rybelsus), a once-daily oral tablet that was approved for marketing in the United States in 2019 for the treatment of type 2 diabetes. Last year, the medium- and high-dose Rybelsus also successfully completed phase III clinical trials for weight loss, progressing ahead of other companies' GLP-1 products.

Next is Eli Lilly's small molecule GLP-1R agonist Orforglipron, also a once-daily oral tablet, which has entered Phase III clinical trials, closely following Rybelsus in terms of development progress.

In China, Zhibio has increased the bioavailability of orally administered peptide drugs by 2 times through optimizing formulation recipes and drug molecules, combined with the QLLong ultra-long-acting technology platform and the QLOral oral peptide technology platform. Zhibio is developing a new generation of oral GLP-1 product—ZT006, primarily for the treatment of diabetes and obesity, by optimizing formulation recipes and drug molecules. The optimized ZT006 exhibits high bioavailability and is expected to become the next generation of oral GLP-1 products following oral semaglutide.

Gaurav Gupta, Managing Partner of J.P. Morgan Asset Management, once stated that the future treatment of obesity is unlikely to be dominated by a stable duopoly, believing that "there will be other winners." So, who will become the competitors of Eli Lilly and Novo Nordisk, and how will the future weight-loss drug market change? We will continue to keep an eye on it.