Obesity is a chronic complex disease contributing to the development of various obesity-related comorbidities, such as metabolic syndrome and dysfunction, type 2 diabetes, cardiovascular diseases, depression, and certain cancer forms [1]. This disease burden can significantly impair health-related quality of life [2]. The prevalence of obesity in adults, defined as a body mass index of 30 or higher (calculated as weight in kilograms divided by height per square metre), has risen from 30% in 1999 to 42% in the US. It is expected to affect almost one in two adults by 2030 [3]. While lifestyle management remains the first-line treatment for obesity, it is often limited by counterregulatory physiological changes that make sustained weight loss challenging. Although bariatric surgery is currently the most effective weight loss intervention, it is expensive and associated with a risk of complications [4].
Nutrient-stimulated hormone-based medications involve the complex interplay of pancreatic (such as glucagon and amylin receptor agonists) and gastrointestinal hormones [such as glucagon-like peptide-1 receptor agonists (GLP-1RA) and glucose-dependent insulinotropic peptide RA (GIP-RA)] to treat obesity and metabolic disorders. Currently, two once-weekly GLP-1RA-based therapies are available for antiobesity treatment (semaglutide (Wegovy®) and tirzepatide (Zepbound™). They act centrally in the hypothalamus by reducing appetite and increasing the feeling of early satiety. In addition, GLP-1RAs act as a key determinant of blood glucose homeostasis due to their abilities to slow gastric emptying, to enhance pancreatic insulin secretion, and suppress pancreatic glucagon secretion [5]. Currently available antiobesity treatments are primarily based on unimolecular [6], and dual molecular [7] hormone-based medications, offering mean weight loss of approximately 15–21% [8], [9]. However, gastrointestinal side effects, such as nausea, vomiting, and diarrhoea have been reported with GLP-1RAs, and were a common cause of treatment discontinuation in clinical trials [10], [11]. Triple agonists [12] such as GLP-1RA, GIP-RA plus glucagon-RA are in development and may show comparable efficacy in weight loss to tirzepatide by targeting multiple pathways involved in energy regulation [13]. However, studies with existing GLP-1RAs have shown discontinuation rates of up to 30% within 1 month, and up to 60–70% within 12 months of initiation [14].
Amylin is a pancreatic peptide hormone co-released with insulin from pancreatic β-cells in response to nutrient intake. It induces satiety and slows gastric emptying by acting on regions of the brain and restoring sensitivity to the hormone leptin [15], [16].
The amylin analog cagrilintide, which is still in clinical development, has demonstrated efficacy in metabolic diseases [17], [18] and may represent an alternative to GLP1-RA-based monotherapy in overweight and obesity alone or in combination with the GLP-1RA based treatment such as cagrilintide and semaglutide (CagriSema), to achieve sustained weight loss. The complementary mode of actions of amylin-analogues and GLP-1RAs (CagriSema) appear to be a promising combination therapy with weight loss of up to -15.6% after 32 weeks of treatment, comparable to that of tirzepatide [19]. Amylin analogs in combination with gastrointestinal hormones may have the potential to further close the gap with bariatric surgery outcomes [20].
Petrelintide (ZP8396) is a 36-amino-acid acylated peptide, based on the peptide sequence of human amylin [21] with chemical and physical stability at neutral pH, minimizing fibrillation [22]. Petrelintide showed potent balanced agonistic effects on both amylin and calcitonin receptors, being in clinical development for once-weekly subcutaneous (SC) administration as a monotherapy [23], for the treatment of overweight and obesity. The substance also allows for potential co-formulation with other hormone peptides, presenting a novel approach to weight management [24].
The Data of the phase 1 single ascending dose trial suggest that the dose was well tolerated and showed potential to reduce body weight [25].
Petrelintide was investigated in this double-blind, placebo-controlled trial to evaluate its safety and tolerability administered as multiple ascending SC doses in healthy people with overweight and obesity in order to identify the maximum tolerated dose. In addition, pharmacokinetic (PK) and pharmacodynamic (PD) properties of petrelintide were evaluated.
Data of the phase 1b multiple ascending dose (MAD) trial was presented (click here to find the presentation) at the Obesity Week (Obesity Society), November 3-6, 2023 in San Antonio, Texas. The abstract is also published online in the Abstracts in Journal - ObesityWeek®.
Forty-eight healthy participants (79% male, median age: 49 years, BMI: 29.9 kg/m2, body weight: 92 kg) were randomized (3:1) within three cohorts. 16 weeks of dosing were used with up-titration every second week to reach different maintenance doses of twelve (2.4 mg), eight (4.8 mg) and six (9.0 mg) weeks, respectively.
Petrelintide was well tolerated with no serious or severe adverse events (AEs). All gastrointestinal (GI) AEs were mild, except for two moderate events (nausea and vomiting) reported in one participant, who discontinued treatment after the third dose; there were no other treatment discontinuations due to AEs. No other events of vomiting, with two events of diarrhea, both mild, occurred. Nausea was reported in 17-33% for petrelintide vs. 17% for placebo. All injection site reactions were mild. The majority occurred in two participants (63%). The most common side effect reported by petrelintide-treated participants was a mild decrease in appetite. Nausea mainly had onset in the dose escalation phase.
There were no clinically significant findings for vital signs, ECG, physical examinations, or clinical laboratory assessments. Mean pulse rate showed a decrease of approximately 5 beats per minute lower at the end of treatment compared to baseline for all cohorts compared to placebo. In addition, there was a trend for decrease for all cohorts in mean systolic and diastolic blood pressure similar to placebo. No participants developed antidrug antibodies.
The pharmacokinetic shows a low within-dose group variation with dose proportionality for the maximum concentration (Cmax) and at the end of each dosing interval (AUC tau) at steady state for the dose range tested (0.6 mg to 9.0 mg). The terminal half-life was approximately 10 days (240 hours), which shows that is suitable for once weekly dosing. Bioavailability following SC dosing had previously been determined to be 85%.
The efficacy for all maintenance doses of petrelintide (2.4 mg, 4.8 mg and 9.0 mg) showed a greater decrease in body weight than was observed for petrelintide treatment groups compared to placebo. After 16 weeks of treatment the observed mean change from baseline in body weight was -4.8%, -8.6% and -8.3%, respectively for petrelintide versus -1.7% for placebo.
aEOT includes measurements at the EOT visit, performed at 24 or 25 weeks after dosing, and also performed for participants discontinuing treatment early.
bOne participant had one extra week at 7.5 mg, and thereby only five weeks on maintenance dose at Week 16.
CI=confidence interval; EOT=end of trial.
A 16-week treatment with petrelintide at maintenance doses of up to 9.0 mg demonstrated a favorable safety and tolerability profile. Gastrointestinal adverse events were mostly mild, transient, and occurred during dose escalation, with only one participant discontinuing treatment due to gastrointestinal symptoms after the third dose. Additionally, no antidrug antibodies were detected. Petrelintide exhibited dose proportionality across the full range tested, supporting its suitability for once-weekly dosing.
Clinically meaningful body weight reductions were observed, with petrelintide achieving up to -8.6% weight loss compared to -1.7% with placebo after 16 weeks. These results position petrelintide as a rising star in the treatment of obesity, offering efficacy comparable to current GLP-1 receptor agonists but with superior tolerability. Its potential as a stand-alone treatment or in combination with other peptide hormones will be further explored in phase 2 obesity trials, where long-term safety and efficacy will be evaluated.