GLP-1’s have emerged as a powerful agent in the treatment of population-level disease states. And there appears to be some hidden depths in regard to their potential to address serious conditions upstream of their initial indications.
Here are two combinations that show promise, one inside a company and another in the laboratory that addresses neurodegeneration.
Viking Therapeutics’ VK2809 and VK2735
The field of GLP-1 (glucagon-like peptide-1) receptor agonists has shown significant promise in treating metabolic disorders, notably type 2 diabetes and obesity. Recent developments in this area have demonstrated the potential of GLP-1-based combination therapies to enhance therapeutic outcomes, and there has been an expansion in upstream indications that are addressable with GLP-1s, notably heart disease and sleep apnea. Viking Therapeutics (VKTX) stands out as an emerging leader in this treatment arena, innovating with its drug candidates VK2809 and VK2735.
VK2809 is a liver-directed thyroid hormone receptor beta (TRβ) agonist. It targets hepatic lipid metabolism, thereby reducing cholesterol and triglycerides. The drug has shown efficacy in animal models and early-stage clinical trials, indicating potential benefits for patients with non-alcoholic steatohepatitis (NASH) and other lipid-related disorders. VK2809’s unique liver-targeting mechanism minimizes systemic side effects, which enhances its therapeutic profile compared to non-selective thyroid hormone analogs.
VK2735 is a dual agonist of GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptors. This dual action is designed to enhance insulin secretion, improve glucose homeostasis, and reduce body weight more effectively than GLP-1 monotherapy. Preclinical studies have shown promising results in terms of weight loss and glucose control, suggesting VK2735’s potential to address the unmet needs in obesity and type 2 diabetes treatment.
Related: What is Viking Therapeutics Worth?
Mechanistic Synergy and Clinical Potential
Combining VK2809 with VK2735 presents a compelling therapeutic strategy. VK2809’s lipid-lowering effects complement VK2735’s glucose and weight management capabilities, offering a holistic approach to treating metabolic syndrome—a cluster of conditions including increased blood pressure, high blood sugar, excess body fat around the waist, and abnormal cholesterol levels. The synergistic action of these drugs could lead to more comprehensive management of these interrelated conditions. Early-stage clinical trials have demonstrated the safety and efficacy of VK2809, with significant reductions in LDL cholesterol and liver fat content. VK2735 has similarly shown best-in-class results in clinical trials in terms of weights loss and side effects.
The combination therapy aims to leverage these individual benefits, potentially offering a superior treatment option that addresses multiple facets of metabolic syndrome.
NMDA Receptor Plus GLP-1
The N-methyl-D-aspartate (NMDA) receptor, a glutamate-activated cation channel, is broadly expressed in neurons in the brain. Historically, small-molecule drugs targeting the NMDA receptor were investigated for their potential in inducing weight loss. However, these early attempts faced significant challenges. The primary hurdle was the adverse physiological and behavioral effects associated with NMDA receptor antagonists, which hindered their translational viability.
A recent study published in Nature has reopened the potential for NMDA receptor-targeted therapies by combining an NMDA receptor antagonist, MK-801, with a GLP-1. This combination has demonstrated potent weight loss effects in preclinical models without the adverse side effects previously observed with NMDA antagonists alone. This breakthrough suggests a novel therapeutic pathway for weight loss, which could be of significant interest given the global obesity epidemic.
Mechanism of Action and Potential Benefits
The NMDA receptor plays a crucial role in synaptic plasticity, learning, and memory. By modulating this receptor, MK-801 impacts neuronal excitability and transmission. However, its use has been limited due to side effects like psychotomimetic symptoms. The GLP-1 agonist, on the other hand, is a well-established therapeutic agent for type 2 diabetes and obesity, known for its ability to enhance insulin secretion and promote satiety. The combination of MK-801 with a GLP-1 agonist leverages the complementary mechanisms of these two agents. While MK-801 modulates neuronal activity, the GLP-1 agonist mitigates adverse effects and enhances the therapeutic profile. The study in Nature has shown that this combination induces significant weight loss and improves neuronal plasticity, which may have long-lasting benefits for patients with neurodegenerative conditions such as Alzheimer’s disease (AD).
Implications for Alzheimer’s Disease
AD is characterized by progressive neuronal loss and cognitive decline. Enhancing neuronal plasticity could slow or even partially reverse these degenerative changes. The combination therapy’s potential to alter neuronal plasticity opens new avenues for AD treatment. If this combination can be translated from preclinical models to clinical settings, it could represent a dual-purpose therapeutic approach, addressing both obesity and neurodegeneration.
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