Obesity and its associated health problems, such as type 2 diabetes and cardiovascular disease, represent a major global health crisis. While lifestyle changes can help prevent obesity, reversing the condition once it's established is challenging. The emergence of glucagon-like peptide-1 (GLP-1) agonists like semaglutide has provided a pharmacological approach to treating obesity. However, there is a need for alternative and complementary therapies to improve long-term outcomes and reduce side effects. A promising new molecule, SANA (5-(2-nitroethenyl)salicylic acid), has emerged as a potential therapeutic strategy for treating obesity and metabolic syndrome.
Understanding the Role of Incretins in Weight Management
Incretin hormones, such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), play a vital role in regulating appetite and blood sugar levels. These hormones are released in the intestine when nutrients are present, boosting insulin production and slowing down stomach emptying, which leads to a feeling of fullness. Medications like GLP-1 agonists and GIPs mimic these effects, reducing appetite and promoting weight loss. While drugs like semaglutide and tirzepatide (GLP-1 agonists) were initially used to treat type 2 diabetes, their weight loss benefits have been recognized, leading to the development of medications like Mounjaro and Wegovy for weight management.
The Promise of Nitrated Unsaturated Fatty Acids
Nitrated unsaturated fatty acids have shown beneficial metabolic effects in preclinical models of obesity. Their pharmacological action stems from their reactive nitroalkene group, which influences multiple signaling pathways. By transferring this nitroalkene group to molecular structures with known pharmacological effects, researchers have created molecules with enhanced beneficial signaling properties and emergent properties.
SANA: A Nitroalkene Derivative of Salicylate
SANA, a nitroalkene-based small molecule, utilizes salicylate as a scaffold. Salicylate, a precursor to aspirin, has been used to reduce inflammation and relieve pain. While high doses of salicylate have shown modest effects on weight gain in obese mice, SANA demonstrates significantly greater effects on weight loss and protection against diet-induced obesity (DIO).
SANA's Mechanism of Action: Non-Shivering Thermogenesis
SANA stimulates non-shivering thermogenesis in both brown and white adipose tissue, a unique property that is independent of uncoupling protein 1 (UCP1) and AMPK activation. This effect is lost after creatine depletion. Studies on Ckmt1 knockout mice have shown impaired thermoregulation after SANA treatment, which can be rescued by thermoneutral housing.
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Preclinical Evidence: SANA Prevents Diet-Induced Obesity
In preclinical studies, SANA has demonstrated the ability to protect mice from diet-induced obesity (DIO). Mice treated with SANA showed decreased fat accumulation in adipose depots and an increased percentage of lean mass. SANA did not affect normal growth, total food consumption, stool mass and calories, digested energy, or activity levels.
SANA Protects Against Metabolic Damage
SANA protects against DIO-associated metabolic damage. The livers of mice fed a high-fat diet (HFD) and treated with SANA had normal macroscopic appearance, indistinguishable from the livers of lean, age-matched control mice. SANA treatment also abrogated DIO-mediated elevation in total liver weight induced by a HFD. Analysis of liver transaminases in plasma showed complete protection from obesity-related liver damage. Assessment of glucose management after DIO revealed that SANA protected mice from elevated blood glucose levels.
SANA improved impaired glucose tolerance, decreased insulin levels, and increased insulin sensitivity. Leptin and free fatty acid levels were also improved in SANA-treated mice. Metabolization of SANA in vivo led to formation of a saturated form of the molecule 5-(2-nitroethyl)salicylic acid (named metabolite 1, M1); however, treatment of mice with M1 had no effect on DIO and glucose management, confirming the need of the reactive nitroalkene group for the metabolic effect of SANA. The metabolic effects of SANA are AMPK independent.
SANA Effectively Treats Established Obesity
SANA was administered to adult mice after obesity was established (5 weeks of HFD). SANA-treated mice lost weight while cumulative food intake was not affected, demonstrated diminished basal glycaemia, showed amelioration of glucose intolerance, and showed no signs of hepatic steatosis.
Clinical Trial Results: Safety and Early Efficacy of SANA
A Phase 1a/b clinical trial evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of SANA in healthy lean individuals and participants with obesity. The trial demonstrated that SANA was safe and well-tolerated at all dose levels, with no serious adverse events reported. Patients receiving SANA experienced a statistically significant reduction in body weight compared to placebo, along with improvements in fasting glucose and insulin resistance. These metabolic improvements were observed after just two weeks of treatment and occurred without any significant changes in diet or activity levels.
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SANA Preserves Lean Muscle Mass
Unlike GLP-1 receptor agonists, which are associated with muscle wasting and loss of lean mass, SANA has been shown in preclinical models to preserve and even increase lean muscle mass while reducing fat mass. These effects are attributed to SANA’s unique mechanism of action of enhancing creatine-dependent thermogenesis and mitochondrial respiration in adipose tissue without reducing food intake.
Eolo Pharma: Pioneering SANA's Development
Eolo Pharma, a clinical-stage biotechnology company, is developing SANA as a therapy for obesity and metabolic disease. The company's research focuses on targeting underexplored metabolic pathways to increase energy expenditure and improve insulin sensitivity.
Future Clinical Trials
Eolo Pharma plans to initiate Phase 2 clinical trials in 2025 to evaluate SANA’s long-term safety and efficacy as both a standalone and combination therapy for metabolic disease.
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