In 2023, Pfizer successively terminated the clinical development of two oral GLP-1 small molecule agonists, Lotiglipron and danuglipron (twice a day). After the disappointment, Pfizer decided to try again. On July 11, 2024, Pfizer announced that based on the results of the ongoing Phase 1 pharmacokinetic study, it has determined to advance its reformulated version of danuglipron (once a day).

The study aimed to explore the PK and safety of the original formulation of danuglipron and three reformulated versions of danuglipron (different doses/releases rates) after a single dose administration.

The results support the pharmacokinetic characteristics of once-daily dosing, and its safety is consistent with previous studies of danuglipron, with no increase in liver enzymes observed in more than 1,400 study participants. Therefore, Pfizer plans to initiate dose optimization studies for the reformulated version of danuglipron in the second half of 2024 to evaluate the efficacy and safety of multiple doses.

Affected by the news, Pfizer’s stock price rose by 3.1% at the beginning of the trading day, with a closing increase of 1.09%. Correspondingly, the stock prices of Eli Lilly and Novo Nordisk fell. (Not a major influencing factor)

01

The popularity of GLP-1 is self-evident. According to Pfizer’s estimates, the weight loss drug market is expected to grow to about 130 billion US dollars in the next decade, with oral tablets expected to account for about one-third of the market. Such a large piece of the cake is irresistible to anyone.

Some industry insiders humorously say, “PD-1 takes a bath, GLP-1 goes swimming,” implying that whether it’s Biotech or MNC, there should be at least one GLP-1 project in the pipeline. Pfizer is no exception, but its R&D process has not been smooth.

In June 2023, Pfizer announced the termination of the clinical development of once-daily Lotiglipron, as the pharmacokinetic data showed that the treatment group had elevated transaminases, a sign of liver cell damage.

However, this was just the beginning. In December 2023, Pfizer announced again the termination of the clinical development of another oral GLP-1 small molecule agonist, danuglipron (twice a day), due to safety issues.

In its Phase IIb study for obesity, the incidence of gastrointestinal reactions in the treatment group was high (nausea 73%, vomiting 47%, diarrhea 25%), and the discontinuation rate at different doses was over 50%, much higher than the approximately 40% rate in the placebo group, indicating that the drug had poor tolerability in some patients.

Now, although Pfizer has decided to “revive” danuglipron and launch the QD (once-daily) improved version, whether it can solve the safety issues is still unknown.

02

Currently, in Pfizer’s clinical pipeline, there are three obesity/diabetes candidate products. In addition to danuglipron, there is another oral GLP-1 receptor agonist, PF-06954522, which is still in Phase 1 of clinical trials.

As for another candidate, PF-07976016, the target has not been disclosed and is also in Phase 1 of clinical trials. Such clinical progress undoubtedly lags far behind competitors.

Even if Pfizer successfully resolves the safety issues without sacrificing the previous efficacy of danuglipron, will the market still give a chance?

So far, the oral semaglutide Rybelsus is still the only oral GLP-1RA on the global market, but Eli Lilly’s small molecule GLP-1R agonist, Orforglipron, is also following closely, and like danuglipron, it is a once-daily oral tablet, currently in Phase III.

Many MNCs have chosen to pick the fruit directly, such as Roche’s acquisition of Carmot Therapeutics to quickly achieve the layout of oral GLP-1RA. As for domestic companies, the clinical progress of oral GLP-1RAs such as Structure Bio’s GSBR-1290, Hengrui’s HRS-7535, and Salubris’ SAL0112 has all surpassed Pfizer’s improved version of danuglipron.

In the future, whether Pfizer can “get a slice of the icing on the cake” remains to be seen.

【Editor’s Note】This is quick translation of a Chinese article published on DrugTimes. To read the original article, please click here. All comments are highly welcome. Many thanks!