VK2735
Dual GLP-1/GIP Receptor Agonist

Metabolic Disorders

Overview & Profile

We are developing a unique series of novel dual agonists of the glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors for the potential treatment of various metabolic disorders such as diabetes, obesity and NASH. Our lead clinical program’s drug candidate is VK2735, currently in a Phase 1 clinical trial.

The Phase 1 trial of VK2735, initiated in January 2022, is a randomized, double-blind, placebo-controlled, single ascending dose (SAD) and multiple ascending dose (MAD) study in healthy adults. The primary objectives of the study include evaluation of the safety and tolerability of single and multiple doses of VK2735 delivered subcutaneously, and the identification of VK2735 doses suitable for further clinical development. Viking selected VK2735 from a series of internally developed dual GLP-1/GIP receptor agonists evaluated as part of a program focused on the development of best-in-class therapies for metabolic diseases. The results of certain in vivo studies from this program were recently presented at ObesityWeek® 2021, highlighting the promising effects observed following treatment with VK2735 and other compounds from the series. Data demonstrated improvements in the metabolic profile of diet-induced obese (DIO) mice treated with Viking’s compounds as compared to control cohorts.

GLP-1 and GIP are gut hormones secreted from intestinal L cells and K cells, respectively. Together, these hormones account for most of the enhanced insulin secretion observed in healthy adults after a meal.¹ The receptors have complementary distribution and activities.²

GLP-1/GIP Receptor Co-Activation and Downstream Effects

Activation of the GLP-1 receptor has been shown to decrease glucose, reduce appetite, lower body weight and improve insulin sensitivity in patients with type 2 diabetes, obesity, or both. Semaglutide is a GLP-1 receptor agonist that has been approved by the U.S. Food and Drug Administration (FDA) and is currently marketed in various dosage strengths and forms as Ozempic®, Rybelsus®, and Wegovy®. More recently, research efforts have explored the potential co-activation of the GIP receptor as a means of enhancing the therapeutic benefits of GLP-1 receptor activation. Tirzepatide is a dual GLP-1/GIP receptor agonist that has been recently approved by the FDA and is currently marketed as Mounjaro™. There is growing excitement around the therapeutic promise of single agents designed to target multiple metabolic receptors, and preclinical data thus far suggest that VK2735 has best-in-class potential as a dual GLP-1/GIP agonist.

Preclinical Data

Viking presented 2 posters (#206³ and #207⁴) with preclinical data from a series of internally developed dual agonists of the GLP-1 and GIP receptors at ObesityWeek® 2021 (November).⁵ The presentations highlight the effects of treatment on body weight and metabolic profile in diet-induced obese (DIO) mice as compared to control cohorts treated with vehicle, the GLP-1 agonist semaglutide, or the dual GLP-1/GIP agonist tirzepatide.

The results of the studies demonstrate that addition of GIP receptor activity improves upon the observed effects resulting from activation of the GLP-1 receptor alone in DIO mouse models. Weight loss, glucose, and insulin effects are enhanced in the Viking series of dual-agonist compounds compared to the effects observed with the GLP-1 agonist comparator, semaglutide, when administered at the same dose for the same time period.³ In separate studies, the effect sizes observed with the Viking series of dual agonists were similar to those observed following treatment with tirzepatide, a dual GLP-1/GIP receptor agonist. Reductions in liver fat content were generally numerically larger among animals treated with Viking compounds relative to liver fat reductions observed among tirzepatide-treated animals.⁴

Overweight and Obesity⁶

Overweight and obesity are defined as abnormal or excessive fat accumulation that may impair health. For adults, the definition of overweight is a body mass index (BMI) ≥ 25, and obesity is a BMI ≥ 30 (BMI is defined as a person’s weight in kilograms divided by the square of his height in meters, kg/m²).

Some recent (2016) global estimates are:

• More than 1.9 billion adults aged 18 years and older were overweight. Of these over 650 million adults were obese.
• 39% of adults aged 18 years and over (39% of men and 40% of women) were overweight.
• Overall, about 13% of the world’s adult population (11% of men and 15% of women) were obese.
• The worldwide prevalence of obesity nearly tripled between 1975 and 2016.

Some of the common health consequences of overweight and obesity are cardiovascular diseases (mainly heart disease and stroke), diabetes, musculoskeletal disorders (especially osteoarthritis, a highly disabling degenerative disease of the joints), and some cancers.

References

1. Frias JP, Bastyr III EJ, Vignati L, Tschöp MH, et al. The Sustained Effects of a Dual GIP/GLP-1 Receptor Agonist, NNC0090-2746, in Patients with Type 2 Diabetes. Cell Metab. 2017;26(2):343–352 (link).   
2. Samms RJ, Coghlan MP, Sloop KW. How May GIP Enhance the Therapeutic Efficacy of GLP-1? Trends Endocrinol. Metab. 2020;31(6):410-421 (link).
3. Yagiz K, Barker G, Barnes M, Stevens E, et al. Novel Co-agonists of GLP-1 and GIP Receptors Produce Robust Weight Loss in a Rodent Model of Obesity. Poster (#206) presented at the annual meeting of The Obesity Society (ObesityWeek® 2021) (link).
4. Yagiz K, Barker G, Barnes M, Stevens E, et al. Novel Dual Incretin Receptor Agonists Reduce Body Weight and Improve Metabolic Profile in DIO Mice. Poster (#207) presented at the annual meeting of The Obesity Society (ObesityWeek® 2021) (link).
5. Viking Therapeutics Presents Preclinical Data on Novel Dual GLP-1/GIP Agonists at ObesityWeek® 2021. Viking Therapeutics press release, 11/1/2021 (link).
6. World Health Organization (WHO): Obesity and overweight (link).