VK2735 (Subcutaneous & Oral Formulations)
Dual GLP-1/GIP Receptor Agonist
Obesity and 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 obesity, NASH, and certain rare disorders. Our lead clinical program’s drug candidate is VK2735.
In September 2023, we initiated the Phase 2 VENTURE trial of VK2735 in patients with obesity. The Phase 2 VENTURE trial is a study intended to evaluate the safety, tolerability, pharmacokinetics, and weight loss efficacy of VK2735, administered subcutaneously, once weekly. The 13-week trial was designed to enroll approximately 125 adults who are obese (BMI ≥30 kg/m2), or adults who are overweight (BMI ≥27 kg/m2) with at least one weight-related comorbid condition. Due to heightened clinician and patient interest, the trial’s enrollment size was increased to 176 from the original target.
In February 2024, we announced that the Phase 2 VENTURE trial successfully achieved its primary endpoint and all secondary endpoints, with patients receiving VK2735 demonstrating statistically significant reductions in body weight compared with placebo. Additionally, the study showed VK2735 treatment to be safe and well tolerated with the majority of treatment emergent adverse events (TEAEs) being categorized as mild or moderate. Based on these findings, Viking intends to meet with the FDA and discuss next steps in the development of VK2735.
The VENTURE study follows a promising initial Phase 1 data, announced during the first quarter of 2023. This Phase 1 trial, evaluating VK2735 (dosed subcutaneously) for metabolic disorders, demonstrated an encouraging safety and tolerability profile as well as positive signs of clinical benefit.
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 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
Oral Formulation of VK2735
During the first quarter of 2023, Viking initiated a Phase 1 multiple ascending dose (MAD) clinical study to evaluate a novel oral formulation of VK2735. The company believes the potential to provide both a subcutaneously injected and an oral dosage form represent a significant expansion of the opportunity for VK2735.
The Phase 1 MAD study of oral VK2735 is an extension of the company’s Phase 1 single ascending dose (SAD)/MAD trial of VK2735 administered subcutaneously mentioned above. The oral portion of the trial is a randomized, double-blind, placebo-controlled study in healthy adults with a minimum body mass index of 30 kilograms per meter squared. The primary objective of the study was to evaluate the safety and tolerability of VK2735 administered as an oral tablet once daily for 28 days. Exploratory pharmacodynamic measures included assessments of changes in body weight and other metrics.
In March 2024, we announced positive results from this Phase 1 MAD clinical trial of the oral tablet formulation of VK2735. Cohorts receiving VK2735 demonstrated dose-dependent reductions in mean body weight from baseline. Cohorts receiving VK2735 also demonstrated reductions in mean body weight relative to placebo. In addition, oral VK2735 demonstrated encouraging safety and tolerability following 28 days of once-daily dosing, and no serious adverse events (SAEs) have been reported to date. Based on these Phase 1 results, the company plans to initiate a Phase 2 trial with the oral formulation of VK2735 in obesity later in 2024.
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 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 glucose-dependent insulinotropic peptide 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 approved by the FDA and is currently marketed in various dosage strengths and forms as Mounjaro® and Zepbound®.
Clinical Data: Subcutaneous VK2735
In September 2023, Viking initiated the Phase 2 VENTURE trial of VK2735 in patients with obesity. During the first quarter of 2024, the company announced positive top-line results from this study in which patients receiving weekly doses of VK2735 demonstrated statistically significant reductions in mean body weight after 13 weeks, ranging up to 14.7% from baseline. Patients receiving VK2735 also demonstrated statistically significant reductions in mean body weight relative to placebo, ranging up to 13.1%. Statistically significant differences compared to both baseline and placebo were observed for all doses starting at Week one and continuing throughout the 13-week treatment period. Reductions in body weight were progressive through the course of the study, with no plateau observed for weight loss at 13 weeks. All doses of VK2735 also demonstrated statistically significant differences relative to placebo on the key secondary endpoint assessing the proportion of patients demonstrating at least 10% weight loss. Up to 88% of patients in VK2735 treatment groups achieved ≥10% weight loss, compared with 4% for placebo.
VK2735 demonstrated encouraging safety and tolerability following 13 weeks of once-weekly dosing in the Phase 2 VENTURE study. Discontinuation rates were low and well-balanced among patients treated with VK2735 compared with placebo. A total of 23 patients (13%) discontinued treatment in the study, 5 (14%) in the placebo cohort and 18 (13%) among VK2735-treated cohorts.
Among patients receiving VK2735 in the VENTURE study, the majority (92%) reported drug related TEAEs as mild or moderate in severity. The majority of TEAEs that were gastrointestinal (GI) in nature (95%) were also reported as mild or moderate. Nausea was reported among patients receiving both VK2735 (43%) and placebo (20%). Among subjects receiving VK2735, the majority of reported nausea (68%) was characterized as mild (32% moderate, none severe). Vomiting was reported in 25/140 (18%) VK2735-treated patients compared with none reported among patients receiving placebo. GI-related adverse events were generally observed early in treatment, with decreasing frequency upon repeat dosing. Across the combined VENTURE study arms, the weekly rate of nausea did not exceed 5% at any point after the first week of treatment. One patient receiving VK2735 experienced a serious adverse event (SAE) of dehydration that was characterized as related to study drug.
Prior to VENTURE, Viking initiated a Phase 1 SAD and MAD clinical trial of VK2735 in 2022. During the first quarter of 2023, the company announced results from this study, which demonstrated that treatment with VK2735 was safe and well-tolerated when dosed for up to 28 days in healthy obese volunteers. In addition, treatment with VK2735 led to mean weight loss of up to 18 pounds from baseline.
In the SAD portion of the Phase 1 study, VK2735 demonstrated promising safety and tolerability, as well as a predictable pharmacokinetic profile. Following single subcutaneous doses, VK2735 demonstrated a half-life of approximately 170 to 250 hours, a Tmax (time to reach maximum plasma concentration) ranging from approximately 75 to 90 hours, and excellent therapeutic exposures.
Clinical Data: Oral Formulation of VK2735
With regards to the oral formulation of VK2735, Viking initiated a Phase 1 MAD clinical study during the first quarter of 2023. In March 2024, we announced positive results from this study. The 28-day MAD study results highlight positive signs of clinical activity following treatment with oral VK2735. Cohorts receiving VK2735 demonstrated dose-dependent reductions in mean body weight from baseline, ranging up to 5.3%. Cohorts receiving VK2735 also demonstrated reductions in mean body weight relative to placebo, ranging up to 3.3%. For doses ≥10 mg, placebo-adjusted reductions in mean body weight were maintained or improved at Day 34, six days after the last dose of VK2735 was administered, ranging up to 3.6% relative to placebo. An exploratory assessment of the proportion of subjects achieving at least 5% weight loss after 28 days demonstrated that up to 57% of VK2735-treated subjects achieved ≥5% weight loss, compared with 0% for placebo. Based on a preliminary evaluation of weight loss trajectory, the company believes that treatment duration beyond 28 days may provide further reductions in body weight.
In terms of safety and tolerability, oral VK2735 demonstrated encouraging safety and tolerability following 28 days of once-daily dosing. Among subjects receiving VK2735, all treatment emergent adverse events (TEAEs) reported to date have been mild or moderate, with the majority (76%) reported as mild. Similarly, all observed gastrointestinal (GI) adverse events have been reported as mild or moderate, with the majority (79%) reported as mild. Mild nausea was reported in five (14%) VK2735-treated subjects. Vomiting was not reported among any VK2735-treated subjects. Diarrhea was reported in one subject (3%) receiving VK2735 compared with two subjects (20%) receiving placebo. Overall, no clinically meaningful differences were reported for GI-related adverse events among subjects treated with VK2735 compared with placebo. In addition, no serious adverse events (SAEs) have been reported to date.
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
- 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).
- 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).
- 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).
- 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).
- Viking Therapeutics Presents Preclinical Data on Novel Dual GLP-1/GIP Agonists at ObesityWeek® 2021. Viking Therapeutics press release, 11/1/2021 (link).
- World Health Organization (WHO): Obesity and overweight (link).