A novel long-acting Amylin analogue for the management of obesity

Introduction

The prevalence of overweight and obesity is increasing worldwide [1]. Being overweight or obese amplifies the risk of other related diseases which can severely impair quality of life [2, 3]. Weight loss of at least 5−10% has been associated with the prevention of type 2 diabetes as well as with clinically relevant improvements in comorbidities of obesity, including cardiovascular risk factors, asthma, sleep apnoea, non-alcoholic fatty liver disease, and osteoarthritis [4]. 

Obesity Management

Pharmacological weight control remains one of the options for the treatment of obesity. When choosing an anti-obesity drug, comorbidities and contraindications to the drug must be considered, as well as the expected extent of weight loss.

The following anti-obesity drugs have been approved:

• Phentermine/Topiramate (brand name: Qsymia^®): This medication is a combination of phentermine, which suppresses appetite, and Topiramate, an antiepileptic drug that can support weight loss.
• Naltrexone/Bupropion (brand name: Contrave^®): This medication combines an opioid receptor antagonist (Naltrexone) with an antidepressant.
• Orlistat (brand names: Xenical^®, Alli^®): Orlistat works by reducing the absorption of dietary fat in the intestines. It is available in prescription-strength (Xenical^®) and over-the-counter (Alli^®) formulations.

Game Changer in Obesity Management

Recent advances in harnessing the complex interplay of pancreatic (glucagon and amylin) and gastrointestinal [incretins: glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP)] hormones to treat obesity and metabolic disorders have revolutionised the potency of weight management and will continuously expand the available pharmacological spectrum [5].The following novel anti-obesity medications improve weight and metabolic parameters, with variable potency. The majority of these compounds primarily act centrally, reducing appetite and increasing the feeling of early satiety, and secondarily in the gastrointestinal tract by slowing gastric emptying.

Their novel mechanisms of action are primarily based on unimolecular [6], dual [7] or triple agonists [8] such as incretins/glucagon or amylin. The following anti-obesity drugs are currently approved [9]:

• Liraglutide (brand name: Saxenda^®): is a unimolecular GLP-1 receptor agonist. Originally developed as a diabetes medication, liraglutide has been approved at a higher dose for chronic weight management. It works by reducing appetite and increasing feelings of early satiety.
• Semaglutide (GLP-1 receptor agonist) (brand name: Wegovy, 2.4 mg), showed a placebo-adjusted weight reduction of 12.4% after 68 weeks of treatment [10]
• Tirzepatide (brand name: Mounjaro^®) is currently approved as diabetes drug while the approval for weight loss is still pending, a novel dual GIP and GLP-1 receptor agonist met the exploratory endpoint of weight reduction of 25% or more in 36.2% of participants in the 15 mg group after 72 weeks of treatment [11].
• Furthermore, the pancreatic hormone amylin acts to control energy homeostasis and body weight. Cagrilintide is a long-acting amylin/calcitonin analogue that is still in development. It has shown promising body weight reducing effects alone and in combination with the glucagon-like peptide 1 receptor agonist semaglutide [12]. In a phase 1 trial in participants with overweight and obesity, cagrilintide in combination with semaglutide 2.4 mg for 20 weeks led to weight reductions of up to 17.1% [13].

First-in-human data (Phase 1a) of a novel long-acting Amylin analogue for the management of overweight and obesity

Data were presented as poster presentation (download here) at the 83rd Scientific Sessions of the American Diabetes Association, June 23-26, 2023 in San Diego, California. The abstract  is also published online on the journal Diabetes^®.

Aim and Background

This clinical trial with the novel long-acting amylin analogue (ZP8396) was designed to assess safety, pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of ZP8396 for the first time in healthy lean and overweight people [13].

ZP8396 is a long-acting amylin analogue with agonistic effects on both amylin and calcitonin receptors designed for once-weekly dosing and to allow for co-formulation with other peptides, including incretins, such as GLP-1 analogues. Amylin analogues hold potential as both single agents and combination therapies for the treatment of obesity.

Native amylin acts as a satiation signal and is co-secreted with insulin from pancreatic cells following nutrient intake. Due to inhibitory action on gastric emptying and glucagon secretion as well as its stimulation of satiety, amylin plays an important role in the control of food intake and the regulation of postprandial glucose excursions. 

ZP8396 is a synthetic 36 amino acid peptide modified with a C20fatty acid. It is formulated as a solution for injection using ZP8396 as an active ingredient in a concentration of 4 mg/mL. All excipients used are tested in compliance with current compendial standards. An albumin binding moiety on ZP8396 reduces renal clearance and increases the half-life of ZP8396.

Materials and Methods

In this randomized, double‐blind, placebo‐controlled single ascending dose study, 56 healthy male participants with a mean age of 38.1 years and a mean BMI of 25.8 kg/m² were randomized (6:2) within seven cohorts to single once-weekly subcutaneous doses of ZP8396 or placebo ranging from 0.04 to 2.4 mg. 
PK profiles were evaluated from Day 1 until Day 50. Baseline assessments for safety (including anti-drug antibodies) were performed prior to dosing on Day 1 until Day 50. PD characteristics (plasma glucose, insulin, glucagon concentrations and gastric emptying assessment after standardized meal intake, in dose cohorts ≥ 0.7 mg) took place prior to dosing on Day 1, and on Day 5.

Results

Safety and tolerability

ZP8396 was well tolerated in this study, with no serious or severe treatment emergent adverse events (TEAEs) and no withdrawals. Most common related TEAEs were decreased appetite, nausea and vomiting, most of which were mild and transient. Nausea and vomiting only occurred in the two highest dose groups. Number and severity of gastrointestinal TEAEs increased with dose.
No anti-drug antibodies were detected in this single dose trial. 

Pharmacokinetics

PK profiles showed a dose linearity with low variability and an approximately mean half-life of ZP8396 of 10 days. Predicted mean Cmax was on Day 1-3 in higher doses.

Body Weight

After 1 week of observation, mean body weight decreased by 2.6%, 3.6%, and 4.2% from baseline following a single dose of placebo, 0.7, 1.4 and 2.4 mg, respectively. Placebo-treated participants demonstrated a body weight increase of 0.6%.

Pharmacodynamics

A dose-dependent reduction in glucagon release was observed after standardised mixed test meal intake.

Conclusion

ZP8396 was well tolerated in single doses of up to 2.4 mg. A half-life of approximately 10 days is suitable for once weekly dosing:
A single dose of ZP8396 resulted in dose-dependent, consistent and sustained reductions in body weight, with an average body weight reduction of placebo-adjusted 4.8% in the 2.4 mg dose group (highest dose group), supporting the potential as a promising treatment option for obesity.

Trial results from the first part of multiple ascending dose trial of ZP8396 are expected to be released in the second half of 2023. Additional clinical studies of longer duration will be necessary to fully assess the clinical potential of ZP8396 alone or as co-formulation with other peptides, such as GLP-1 analogues.