, in line with patient preference.
One particularly intriguing entry is ARD-101, in development by Aardvark Therapeutics in San Diego, California. Aardvark came out of stealth on May 9 with the announcement of $85 million in new financing. The biopharma will use the money to complete trials of ARD-101 to treat hyperphagia in Prader-Willi syndrome, both to help patients quell the unrelenting hunger that characterizes the orphan disease and as a proof of principle to demonstrate the compound’s complementary mechanism of action to the current glucagon-like peptide 1 (GLP-1) therapies for obesity.
Oral ARD-101 is a bitter taste receptor (TAS2R) that mediates hunger, whereas the GLP-1 drugs mainly influence appetite, said the company’s CEO, Tien Lee, MD.
“If you love chocolate cake, for instance, appetite is driving you to eat that. And if that chocolate cake were to turn magically into dog food, your appetite probably would go to zero. But if that dog food were your only food source, over enough time, hunger would eventually compel you to eat it. That’s how they’re differentially driven.”
He added, “Hunger and appetite approaches are not mutually exclusive. In fact, they’re complementary to each other, and they’re additive in terms of treatment effect.”
Now that the company is out of stealth, expect more published data and updates on ongoing studies, he added.
Here’s a look at other promising oral drugs on the horizon.
Oral Semaglutide
The once-daily 50 mg tablet formulation of this GLP-1 receptor agonist is among the nearest to approval. The formulation was studied for weight loss in individuals with overweight/obesity in the OASIS 1 phase 3a trial. When applying the treatment policy estimand (defined as the treatment effect regardless of adherence), people who took the pill achieved a weight loss of 15.1% over 68 weeks compared with a 2.4% reduction with placebo, and 84.9% achieved a weight loss of ≥ 5% vs 25.8% with placebo, according to the manufacturer Novo Nordisk.
A spokesperson for the company told this news organization that, contrary to earlier reports, the 50 mg pill will be submitted for regulatory approval after results from OASIS 4 are in, “so we have the full data set.” OASIS 4 is investigating the 25 mg oral dose, and results are expected this year.
“The US launch of oral semaglutide for obesity will be contingent on portfolio prioritization and manufacturing capacity,” the spokesperson said. The company can produce semaglutide as a tablet or injectable, but the oral form requires more an active pharmaceutical ingredient. Therefore, production capacities are being expanded globally for both formulations.
Oral Amycretin
Novo Nordisk’s spokesperson said that, as announced in March, results from an exploratory endpoint on body weight change in a phase 1 trial showed an average −13.1% reduction after 12 weeks of treatment with once-daily oral amycretin compared with −1.1% for placebo. The favorable safety/tolerability and pharmacokinetic profile observed in the trial allows for further development of amycretin.
“Moreover,” the spokesperson said, “we are developing the oral small molecule CB1 receptor inverse agonist monlunabant (INV-202), which has shown weight loss potential in phase 1 with a favorable safety and tolerability profile and is currently being investigated in phase 2 in diabetic kidney disease and obesity.”
APH-012
As of April 25, Aphaia Pharma completed enrollment of the first two cohorts in its randomized, double-blind, placebo-controlled proof-of-concept phase 2 trial evaluating a once-daily 12-g dose of its proprietary oral glucose formulation APHD-12 for obesity.
The company also announced that the US Food and Drug Administration (FDA) has approved an expansion of the trial›s protocol to investigate the contribution of circadian effects in weight loss treatment. The new protocol will include additional cohorts, which will be dosed with either 6 g (APHD-006) or 8 g (APHD-008) of Aphaia’s formulation or placebos twice daily. The primary endpoint of the trial is the change from baseline in percent weight compared with placebo. The study will also evaluate exploratory secondary endpoints, which are considered hallmarks of multiple metabolic diseases closely associated with obesity.
The drug candidate is “designed to be released at discrete parts of the small intestine to restore endogenous nutrient-sensing signaling pathways and stimulate the release of the broad spectrum of enteric hormones that control multiple homeostatic functions like appetite, hunger, satiety, glucose metabolism, and energy expenditure,” according to the company’s announcement. “This includes glucagon-like peptide 1, peptide tyrosine-tyrosine, glicentin, and oxyntomodulin, among others.”
Topline data from the first part of the study are expected to be released by the third quarter.
AZD5004
In November 2023, AstraZeneca entered into an exclusive licensing agreement with Eccogene to develop and commercialize ECC5004 (now AZD5004), a tablet formulation of a small molecule GLP-1 receptor agonist, both as monotherapy and in combination with AZD6234, its antiobesity agent that targets the gut hormone amylin.
“We are excited by the potential of AZD5004 as a novel oral small molecule GLP-1 receptor agonist,” a company spokesperson told this news organization. “The phase 1 study has provided us with the confidence to progress development into a phase 2 program studying patients with type 2 diabetes and in obesity. We are in the process of designing these studies and expect to start them in the second half of 2024.”
Ecnoglutide
In January, Sciwind Biosciences announced positive interim results from the first four cohorts of a phase 1 clinical trial of oral ecnoglutide (XW004). Ecnoglutide is a long-acting, cAMP signaling biased, GLP-1 analog being developed for the treatment of obesity and type 2 diabetes.
The phase 1 trial (NCT05184322) is a randomized, double-blind, placebo-controlled multiple ascending dose study that enrolled 42 healthy (cohorts 1-3) and 14 healthy obese (cohort 4) participants in Australia. In cohorts 1-3, target doses were 7 mg, 15 mg, or 30 mg XW004 once daily for 2 weeks; in cohort 4, the target dose was 30 mg XW004 once daily for 6 weeks. Treatment periods included gradual dose escalation to the target doses.
Study participants achieved a mean body weight reduction of −6.8% from baseline, compared with −0.9% for the placebo group, according to the company. Based on the positive results, the study is continuing and will evaluate additional dosing regimens, including once-weekly oral administration in participants with obesity.
The company is also developing an injectable formulation of ecnoglutide.