Ayisha Sharma
News Reporter
Katherine Lewin
News Reporter
Novo Nordisk and Eli Lilly are set to make billions of dollars each year off their GLP-1s, but patients and prescribers are still eager for improved drugs, citing GI side effects, muscle loss and weight gain after stopping treatment
Add in the potential for drugs like Novo’s semaglutide (marketed as Wegovy for weight loss and Ozempic for type 2 diabetes) and Lilly’s tirzepatide (approved as Zepbound for weight loss and Mounjaro for diabetes) to improve cardiometabolic function, and these drugs may tap into what industry insiders are now calling the “obesity plus” or “GLP-1 plus” opportunity.
We take a deep dive into five of the most anticipated next-generation GLP-1s in development and their “plus” potential.
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Will Pfizer’s danuglipron get a second chance?
Pfizer’s once-daily oral drug could offer convenience advantage over Wegovy and Zepbound, which are once-weekly subcutaneous injections.
Small-molecule oral GLP-1s could also have improved safety and tolerability compared with their peptide-based counterparts, a Pfizer spokesperson told Endpoints News. That’s an important consideration, given that safety is exactly what Pfizer struggled with during its first shot developing danuglipron.
Mikael Dolsten
The pharma giant designed danuglipron as a twice-daily drug, but that approach ended in December with poor tolerability in a Phase IIb trial in adults with obesity. The pill had discontinuation rates of more than 50% across all doses compared to 40% discontinuation for placebo. The asset was also linked with high levels of nausea (73%), vomiting (47%) and diarrhea (25%).
Now, a Phase I test of once-daily danuglipron is set to end in May, per clinicaltrials.gov, with PK data due in the first half of this year. Pfizer CSO Mikael Dolsten recently hinted to investors that danuglipron could move straight into Phase III with a lead-in period assuming robust safety data from the Phase I.
AstraZeneca eyes cardiorenal space
AstraZeneca is also exploring the once-daily oral route with ECC5004, which it licensed from Eccogene last year for $175 million upfront and up to $1.83 billion in milestones.
The drug showed encouraging weight loss and glucose reductions versus placebo per preliminary results from the Chinese biotech’s Phase I trial in type 2 diabetes patients. Data from that study have not yet been published and are expected to be presented at an upcoming medical congress.
Sharon Barr
Meanwhile, the pharma giant plans to launch two Phase II studies of AZ-5004 later this year in overweight patients and type 2 diabetes patients.
“Everybody focuses on obesity, but there’s this big segment of people who are not obese, but overweight,” AstraZeneca CEO Pascal Soriot said during the company’s earnings call on Feb. 8. “They only need to lose a bit of weight and they also have metabolic disease, sometimes with [accompanying] organ damage.”
BioPharmaceuticals R&D chief Sharon Barr highlighted Farxiga, the company’s chronic kidney disease and heart failure drug and its experimental oral PCSK9 inhibitor, as potential combination targets for the GLP-1.
Lilly’s “triple G” may offer even more weight loss
Lilly, already one the leading companies in the market, has a potentially more potent successor to Mounjaro with its Phase III drug retatrutide. Unlike the approved therapies that target only GLP-1 or both GLP-1 and GIP, retatrutide also acts on the receptor for a third hormone called glucagon. It’s accordingly been dubbed a “triple G.”
The approach appears to have paid off from the Phase II results, which saw obese patients lose 24% of their body weight after about a year of treatment. Even more compelling, there were also signs that weight loss in patients taking the highest dose of the drug had not yet plateaued.
By contrast, Wegovy saw 15% weight loss at 68 weeks of treatment, and Zepbound achieved 26% weight loss at 88 weeks.
Lilly is also testing retatrutide in Phase III studies for obese patients with knee osteoarthritis and obese patients with and without diabetes, with data readouts expected starting in 2025. The candidate is also in a Phase II trial to see if it can improve renal function in overweight and obese patients with CKD.
A NASH benefit for Boehringer Ingelheim and Zealand’s survodutide?
Survodutide, a glucagon/GLP-1 receptor dual agonist, is in a multitude of studies, including a closely-watched Phase II evaluating the treatment in adults with NASH and liver fibrosis. Data from the trial are expected in the first half of this year.
Back in December, Zealand said survodutide has potential cardioprotective benefits in NASH, thanks to the direct effect of glucagon on the liver. And then at a Goldman Sachs conference in January, Zealand CEO Adam Steensberg said, “The key differentiator would be … if we also generate strong data in NASH.”
Carinne Brouillon
The drug is in two Phase III studies in obesity following a Phase II trial in which patients achieved up to 19% weight loss. One study will have just obese or overweight patients, and the other will focus on patients with obesity and type 2 diabetes.
Boehringer’s head of human pharma, Carinne Brouillon, told Endpoints she sees the differentiator for survodutide as its potential to be “the first anti-obesity medication to reduce appetite while increasing energy expenditure and have a direct impact on the liver.”
The drug is also in a Phase III long-term cardiovascular safety study in some obese/overweight patients with cardiovascular disease and chronic kidney disease, potentially setting it up to compete with Wegovy as a treatment to cut the risk of cardiovascular events.
Could Amgen’s MariTide maintain weight loss?
Amgen’s MariTide might be the earliest-stage obesity drug in this lineup, but the company says it’s showing potential to fix one of the most talked-about issues with GLP-1s — patients who regain weight after stopping treatment.
Patients on the highest dose of MariTide lost an average of 14% of their body weight over 85 days in a Phase I study.
But what stands out in the data is that patients also sustained weight loss after ending treatment. Patients maintained a weight reduction of 11.2% on the highest dose, 150 days after they last took the drug. For those in the trial who took just a single high dose of 840 mg, patients still saw weight reduction of 8.2% at day 92, which the company described as a “prolonged weight-reducing effect.”
Now, Amgen is full speed ahead on development. It added a second part to its ongoing Phase II study of MariTide to explore durable weight loss effects beyond 52 weeks, and it’s got plans for a “very expansive Phase III program.”
Editor’s Note: This article has been corrected to note that data from the Phase I trial of AZ-5004 have not yet been published.
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