New study reveals potential of first-in-class oral therapy to treat diabetes and obesity, without losing muscle mass
Figure 1, published in Cell. Discovery of adrenergic receptor agonists that increase glucose uptake with low cAMP generation
- Novel drug candidate, ATR-258, performs well in preclinical and clinical trials in treating type 2 diabetes and obesity, without loss of muscle mass
- ATR-258 is an oral therapy, making it a straightforward, patient-friendly option over injectable therapies
- Monash University researchers provided preclinical evidence to support ATR-258 as a frontrunner candidate for type 2 diabetes and obesity
A first-in-class drug candidate for the treatment of type 2 diabetes and obesity has been found to boost glucose uptake, increase insulin sensitivity, and preserve muscle mass – mimicking the key aspects of exercise.
The new research, led by the clinical-stage Swedish biotech company Atrogi, and including researchers from the Monash Institute of Pharmaceutical Sciences (MIPS), has been published in Cell. The international team behind the research have detailed the transformative potential of Atrogi’s drug candidate ‘ATR-258’ (referred to as compound 15 in the study), which has already successfully completed a Phase 1 clinical trial.
Bringing together interdisciplinary expertise from around the world, the authors collectively show through both preclinical and clinical studies that ATR-258 not only performs well in treating type 2 diabetes and obesity, it also reduces potential for cardiac, muscular and gastrointestinal side effects compared to standard treatments and more recently developed medications such as semaglutide (e.g. Ozempic, Wegovy).
ATR-258 is a novel drug candidate which elicits a favourable physiological response when it binds to the ‘βeta-2 adrenergic receptor’ (β2-AR), a G protein-coupled receptor (GPCR) known to play a critical role in regulating glucose uptake in skeletal muscle when activated.
The MIPS team, including Emeritus Professor Roger Summers, Dr Dana Hutchinson and Dr Seungmin Ham, provided preclinical evidence by identifying and determining the selectivity, potency and efficacy of select drug candidates, including ATR-258, when they bind to β2-AR.
All of the selected compounds investigated by the MIPS team performed well in preclinical models of diabetes and obesity and demonstrated a lower potential for side effects than current treatments on the market. ATR-258 emerged as the frontrunner candidate due to the way in which it not only treats diabetes and obesity, it also promotes muscle growth.
Professor Summers said the MIPS team were able to describe in the Cell study the ‘pathway-selective agonists’ of the β2-AR that prefer ‘G-protein receptor kinase’ (GRK) coupling, which is essential for promoting glucose uptake into muscle, thus underpinning ATR-258s potential as a more targeted treatment for type 2 diabetes and obesity with fewer side effects.
“GRKs play a crucial role in regulating the activity of GPCRs, so what we were looking for is drug candidates that weakly activate β2-AR and, importantly, have a preference for interacting with GRKs to improve uptake into muscle, rather than interacting with other proteins (i.e. heterotrimeric Gs proteins and b-arrestin) that are responsible for side effects and desensitisation,” Professor Summers said.
“A combination of screening methods led us to the identification of these GRK-biased β2-AR partial agonists, ultimately laying the building blocks for further development of ATR-258 which has now progressed into clinical trials, offering a potentially exciting new oral capsule option for type 2 diabetes and obesity, without commonly associated side effects.”
Type 2 diabetes and associated metabolic disorders represent a huge globally increasing health problem that is expected to affect 7 percent of the global population by 2030. Semaglutide has revolutionised treatment of type 2 diabetes and obesity in recent years, however there is mounting evidence showing that individuals taking these medications may lose a substantial amount of muscle mass alongside fat.
Dr Hutchinson said ATR-258 represents a next generation of therapeutics for the treatment of metabolic diseases and sarcopenia - age-related loss of skeletal muscle mass, strength, and function.
“ATR-258, a synthetic small molecule, has favourable pharmacokinetics and in Phase 1 clinical trials has been administered just once a day as a capsule, making it a straightforward, patient-friendly option over injectable therapies,” Dr Hutchinson said.
“The early stage drug discovery approaches adopted to develop this drug into a viable candidate, combined with the Atrogi-led clinical trials, all show great promise for identifying and developing future drug candidates for metabolic disease and sarcopenia.”
Dr Ham said: “To date, ATR-258 has been a huge collaborative effort right across the drug discovery and development pipeline, from early stage discovery right through to clinical trials. It’s really exciting to be a part of the team behind such a promising new option for people all over the world living with type 2 diabetes and obesity.”
Chief Scientific Officer and Founder of Atrogi Professor Tore Bengtsson said: “This paper is the culmination of over two decades of research into β2-adrenergic receptor signalling and represents a significant advancement in metabolic medicine. For the first time, we’ve shown it’s possible to fully separate the metabolic benefits from the cardiovascular risks – a major hurdle in the development of βeta agonist-based therapies. This opens up new possibilities for treating not just diabetes, but a range of metabolic dysfunction.”
The next step is for Atrogi to advance ATR-258 into two Phase 2 trials to evaluate its effects on body composition, muscle mass and function, and metabolic parameters. The first trial titled ATTRACTIVE-3 will assess proof-of-concept in healthy volunteers, and ATTRACTIVE-4 will evaluate the compound as an add-on therapy to GLP-1 agonists in obese patients.
Also integral to the production of the paper, entitled GRK-biased adrenergic agonists for the treatment of type 2 diabetes and obesity, was Shane Wright, from the Department of Physiology and Pharmacology at the Karolinska Institutet. The publication also includes contributions from other leading research institutions worldwide, including Stockholm University, University of Copenhagen, University of Nottingham and the University of Queensland.