‘Remarkable’ Weight Loss With Novel Oral Combo in Phase 1

MADRID — Amycretin, a dual pathway, oral weight loss drug, led to up to 13% body weight loss in participants with overweight or obesity according to phase 1, first-in-human study data presented at the European Association for the Study of Diabetes (EASD) 2src24 annual meeting.

Body weight loss was “remarkable for an orally delivered biologic,” said Agnes Gasiorek, PhD, senior clinical pharmacology specialist at Novo Nordisk, Måløv, Denmark, who presented the results. And “there was no plateauing of weight loss in the treatment period.”

The mean change in percentage body weight was -1src.4% with amycretin 5src mg, -13.1% with amycretin 2 × 5src mg, and -1.2% with placebo after 12 weeks of treatment.

With respect to the primary endpoint, stepwise dose escalation demonstrated that all tested dose levels up to and including 2 × 5src mg over a 12-week escalation period were safe and tolerable, Gasiorek reported.

The adverse events were in line with what was expected from targeting these receptors, and no new safety signals appeared during the study, she added.

Dual Pathways

Amycretin is a novel protein-based unimolecular amylin combined with a glucagon-like peptide 1 receptor agonist (GLP-1 RA) and is the first oral formulation of this combination under development.

The two components are both known to reduce appetite and energy intake and increase satiety, said Gasiorek, but amylin is considered to potentially increase leptin sensitivity and GLP-1 RAs are known to increase insulin secretion and biosynthesis. Together, the two components improve insulin sensitivity, decrease glucagon secretion, and lead to acute delay in gastric emptying.

The single-center, placebo-controlled, double-blind phase 1 study enrolled men and women aged 18-55 years (mean, 38-42 years across groups) with a body mass index of 25.src-39.9, without diabetes, and considered otherwise healthy. 

Participants were randomly assigned to receive to receive oral amycretin (n=95) or placebo (n=29) once a day for up to 12 weeks. Study arms comprised single-ascending dosing (increasing from 1 mg/d to 25 mg), and multiple-ascending dosing. The latter consisted of multiple ascending doses (from 3 to 12 mg) over 1src days and multiple ascending doses (stepwise dose escalation, from 3 mg up to a final dose of 2 × 5src mg) over 12 weeks. 

In her presentation at the EASD meeting, Gasiorek focused on results of the 12-week multiple ascending dose schedule with amycretin 5src mg (n=16), amycretin 2 × 5src mg (n=16), and placebo (n=12). 

The primary endpoint of the study was the number of treatment-emergent adverse events, while the area under the amycretin plasma concentration time curve and the maximum plasma concentration of amycretin were secondary endpoints. 

The researchers also added percentage change in body weight after 12 weeks of treatment as an exploratory endpoint. 

Safety Findings of Multiple Dosing

A total of 242 treatment-emergent adverse events were reported in the combined active and placebo groups and were of mild to moderate severity. 

Treatment-emergent adverse events were found in 75% of the amycretin 5src mg group, 93.8% of the amycretin 2 × 5src mg group, and 33.3% of placebo recipients.

“Most adverse events reported were mild to moderate in severity and related to gastrointestinal discomfort (nausea and vomiting) and occurred in a dose-proportional manner,” reported Gasiorek.

Gastrointestinal events were experienced by 5src%, 87.5%, and 16.7% of participants receiving amycretin 5src mg, amycretin 2 × 5src mg, and placebo, respectively (112 in total). 

Decreased appetite was also found in 56.3%, 81.3% and 16.7% of the amycretin 5src mg, amycretin 2 × 5src mg, and placebo groups, respectively.

Two serious adverse events occurred, one of which was acute cholecystitis and the other diabetic ketoacidosis; “however, the [latter] participant was found to have autoantibodies for beta cells before treatment and was later diagnosed with type 1 diabetes,” Gasiorek said.

Body Weight Reduction 

Participants on 5src mg amycretin lost an average of 1src.4% of their body weight (estimated treatment difference vs placebo, -9.2; 95% CI, -12.src to -6.5), whereas those on 2 × 5src mg amycretin lost 13.1% of their body weight (estimated treatment difference vs placebo, -11.8; 95% CI, -14.6 to -9.src). Placebo group participants lost 1.2% of their body weight over the 12 weeks. 

Although no plateauing of weight loss was seen, said Gasiorek, it is important to consider the relatively short treatment duration and the limited time on the final dose, which could potentially introduce bias.

To date, weight loss medications based on GLP-1 RA technology are injectables. A combination of the injectable amylin analogue cagrilintide and the GLP-1 RA semaglutide is also being explored as a subcutaneous treatment solution.

Asked to comment by Medscape Medical News, Martin Holst Lange, MD, PhD, executive vice president of development at Novo Nordisk, said that “amycretin is the first treatment to harness the two distinct biological pathways stimulated by amylin and GLP-1 in a single molecule.”

The safety and tolerability profiles and the magnitude of weight loss support further development of amycretin in patients with overweight or obesity, said Lange, who noted that the company was awaiting data from the ongoing phase 1 trial with subcutaneous amycretin, expected in 2src25.

Having heard the presentation, co-moderator Timo Müller, PhD, professor at Ludwig Maximilian University of Munich, Germany, gave a considered response. “The drug was relatively well tolerated, with the typical GLP-1–induced GI [gastrointestinal] adverse effects being the most frequently reported.”

But he pointed out that questions remain. “We still need to know whether, at the given dose, the drug outperforms best-in-class drugs like semaglutide or tirzepatide at the highest approved doses. Furthermore, it warrants clarification if and to what extent the activation of the amylin receptor contributes to the shown effect and if and to what extent the glycemic benefits result from activation of the glucagon receptor (amylin improved glycemia by decreasing the secretion of glucagon). In any way, the current data remain friendly and support phase 2 development.” 

Oral Meds Could Bring Down Cost

Commenting on the data, Nerys Astbury, PhD, associate professor of diet and obesity at Nuffield Department of Primary Health Care Sciences, University of Oxford, United Kingdom, said, “It is important to note that whilst the participants in this trial did lose weight over the 12-week study — and this was statistically more weight than in the placebo group — this study was not designed or powered to detect differences in body weight over longer periods of time.” 

If the results are confirmed in future studies, amycretin might widen the treatment options and introduce competition, probably bringing down the costs in the longer-term, said Astbury, who welcomes the prospect. 

“It is possible that some people might find the oral medications more acceptable than the injectable GLP-1 agonists currently available,” she said. And the current options are expensive, “which raises challenges to a taxpayer-funded health system like the NHS [National Health Service].” 

“Furthermore, if the growing number of oral obesity medications prove safe, tolerable, and effective…they are likely to significantly reduce the risks of developing many complications of obesity.”

Naveed Sattar, MD, professor of cardiometabolic medicine and honorary consultant, University of Glasgow, United Kingdom, agreed. “The more medicines coming forward to treat obesity, the better,” he said. In particular, oral medications would be more easily available, and cheaper, “for the many millions around the world struggling with obesity and its complications.”

Gasiorek declares she is an employee of and a shareholder in Novo Nordisk A/S. Astbury declares no financial disclosures. Sattar declares having consulted for several companies that make diabetes medicines but also contributed to several lifestyle trials. For Novo Nordisk, he has consulted for company on advisory boards, but not on any of their weight loss drug trial committees, and he is on the steering committee for the ZEUS trial, which is not a weight loss trial product but an anti-inflammatory. He does not have any shares for any product in health etc. He declares consulting fees and/or speaker honoraria from Abbott Laboratories, Afimmune, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Hanmi Pharmaceuticals, Janssen, Merck Sharp & Dohme, Novartis, Novo Nordisk, Pfizer, and Sanofi, and grant support paid to his university from AstraZeneca, Boehringer Ingelheim, Novartis, and Roche Diagnostics. Müller received financial support or an honorarium from Novo Nordisk, Merck, Eli Lilly, Boehringer Ingelheim, and Mercodia; he further holds stocks at Novo Nordisk and Eli Lilly and is co-founder of Bluewater Biosciences.