Beyond GLP-1: Emerging Therapies for Obesity Discussed at ADA 2024

Obesity, a chronic disease linked to increased risks of complications and mortality, has spurred significant research into the mechanisms of weight regulation and the gut-brain axis’s role in appetite control. This understanding has paved the way for the development of safe and effective treatments, such as glucagon-like peptide-1 (GLP-1) receptor agonists, which are based on entero-pancreatic hormones. Additionally, several non-entero-pancreatic hormone therapies are under evaluation, offering alternative therapeutic options due to their distinct mechanisms of inducing weight loss. These emerging therapies highlight the expanding landscape of obesity treatment, aimed at addressing the multifaceted nature of the disease.

In this context, many pharmaceutical companies, including Biolexis Therapeutics, Arrowhead Pharmaceuticals, and Viking Therapeutics, among others have presented their pre-clinical data at the American Diabetes Association (ADA) 2024 session. Their contributions are crucial in addressing the most challenging aspects of this new era in obesity management, demonstrating a collective effort to advance therapeutic strategies and improve patient outcomes. 

Below, we highlight some of the important abstracts from the session, showcasing the innovative approaches being developed to combat obesity.

1. MLX-0871: A Potent, Selective AMPK Activator Effective in Obesity and Type 2 Diabetes Models

Biolexis presented compelling data on MLX-0871, a potent, isoform-selective, orally available AMPK activator. This novel drug has demonstrated remarkable efficacy in preclinical models of obesity and type 2 diabetes, underscoring its potential as a groundbreaking treatment for these prevalent conditions.

AMPK, a heterotrimeric Ser/Thr kinase composed of α, β, and γ subunits, serves as a cellular energy sensor activated by upstream enzymes in response to elevated AMP-to-ATP ratios during nutrient deprivation. Influenced by physiological factors such as hormones, cytokines, dietary nutrients, and pathological conditions including obesity, chronic inflammation, and type 2 diabetes, AMPK activation can reduce hepatic and plasma glucose levels, making it a promising target for treating various metabolic diseases.

In a preclinical study, the activation of 12 isoforms of AMPK was assessed using a radiometric HotSpot™ assay. Glucose uptake and Western Blot cell-based assays were conducted on human skeletal muscle, upper arm, white preadipocyte, abdominal, and hepatocyte cells. Male C57BL/6 DIO mice, aged 20 weeks and fed a high-fat diet (60% kcal) for 14 weeks, were used for in vivo experiments. The study compared a vehicle group to two treatment groups receiving oral doses of 10 mg/kg and 30 mg/kg for 30 days, with weight loss and serum glucose regulation measured at regular intervals.

The results demonstrated a dose-dependent stimulation of AMPK activity and enhanced glucose uptake in human tissues. Importantly, MLX-0871 did not activate AMPK in cardiac muscle tissue samples from healthy, obese, and diabetic patients, indicating selectivity for skeletal muscle. These MLX compounds exhibited safety and tissue specificity, suggesting that MLX-0871 may have therapeutic potential for treating metabolic disorders such as obesity and type 2 diabetes.

Thus, this oral small molecule marks a substantial advancement in the therapeutic landscape for metabolic diseases. With promising preclinical results demonstrating AMPK activation and enhanced glucose uptake specifically in skeletal muscle, while maintaining cardiac safety, MLX-0871 holds potential as a targeted therapy for conditions like obesity and type 2 diabetes. The company plans to advance this asset into clinical trials by the second quarter of early 2025, aiming to optimize treatment options for these prevalent and challenging health concerns. This development underscores a promising step forward in addressing the complex metabolic pathways involved in these conditions, potentially offering new hope for patients worldwide.

2. Targeting Metabolic Disease: ARO-INHBE Silences Liver INHBE with siRNA Therapy

Arrowhead Pharmaceuticals unveiled preclinical findings on ARO-INHBE, an RNAi-based therapeutic candidate targeting obesity and metabolic disorders, during the ADA 84th Scientific Session. The presentation highlighted promising advancements in the development of this investigational medicine, emphasizing its potential impact on addressing critical unmet needs in managing obesity-related conditions. Arrowhead’s research underscores ongoing efforts to innovate within the field of RNA interference, aiming to deliver novel treatments that could significantly influence the future landscape of metabolic health interventions.

In a preclinical study, siRNA conjugates targeting hepatic INHBE were developed. Pharmacodynamic properties of ARO-INHBE were assessed in cynomolgus monkeys, and its impact on body weight, composition, glucose homeostasis, and lipid metabolism was evaluated in DIO and db/db mice using a mouse surrogate.

Preclinical findings demonstrate that ARO-INHBE effectively suppresses hepatic INHBE gene expression, a pivotal target identified in genetic studies for treating obesity and metabolic disorders. Administration of INHBE siRNA led to significant reductions: 95% in INHBE mRNA expression, 19% in body weight compared to controls, and 26% in fat mass while preserving lean mass. Thus, the research suggests INHBE knockdown holds promise in mitigating weight gain and enhancing body composition.

Based on these promising preclinical results, Arrowhead intends to seek regulatory clearance by late 2024 to initiate clinical trials for ARO-INHBE. This novel drug, which targets the INHBE gene, aims to address limitations observed with current agents, such as minimizing loss of lean mass and reducing adverse gastrointestinal effects at higher doses. If successful, ARO-INHBE could represent a significant advancement in the treatment of metabolic diseases, including obesity and diabetes.

3. Enhancing Body Composition: SRK-439 Synergizes with GLP-1RAs in Obese Mice

Scholar Rock has unveiled compelling new preclinical findings demonstrating that SRK-439 holds promise in enhancing lean mass and promoting favorable body composition after cessation of GLP-1 receptor agonist therapy. 

In a study using a mouse model of diet-induced obesity (DIO), concurrent treatment with the selective anti-myostatin antibody SRK-439 alongside the GLP-1RA semaglutide (sema) preserved lean mass during weight loss. After semaglutide withdrawal, continued SRK-439 treatment maintained a favorable body composition, suggesting a potential strategy to mitigate lean mass loss associated with GLP-1RA therapies in obesity management.

SRK-439’s ability to preserve lean mass during weight loss addresses a significant challenge in obesity treatment. This preservation of lean mass not only enhances the durability of weight loss but also contributes to long-term health benefits. Such advancements underscore the potential for SRK-439 and similar therapies to revolutionize the landscape of obesity treatment in the years ahead.

4. Cutting-edge Co-Agonists: Novel Approach Reduces Food Intake and Body Weight in Rodents

Viking Therapeutics has showcased preclinical data emphasizing its dual agonists of amylin and calcitonin receptors (DACRAs), underscoring their potential as an appealing target for therapeutic interventions in obesity.

The study findings indicate that Viking Therapeutics’ DACRAs significantly decreased food intake in lean rats up to 72 hours after a single subcutaneous dose, with treated animals showing body weight reductions of up to 8% compared to controls. In a separate study using diet-induced obese (DIO) mice, treatment with Viking’s co-agonists over 24 days led to weight reductions comparable to those achieved with cagrilintide. Furthermore, these compounds demonstrated improvements in key metabolic indicators, including blood glucose levels, highlighting their potential therapeutic efficacy in managing obesity and related metabolic conditions.

These preclinical findings emphasize the strategic basis for Viking Therapeutics to further advance its internal program developing dual amylin and calcitonin receptor agonists. They highlight the company’s commitment to pioneering novel therapies for obesity, leveraging potential best-in-class attributes. These results provide a strong foundation for Viking to explore differentiated treatment avenues, aiming to address unmet needs in obesity management through innovative therapeutic approaches.

5. S-309309: Boosting Intestinal Fat Burning for Metabolic Gains in DIO Mice

Shionogi presented positive data on its novel selective MGAT2 inhibitor, S-309309, at the ADA 2024 conference. In the study, mice were subjected to a high-fat diet (HFD) for 4 weeks to induce diet-induced obesity (DIO). S-309309 was orally administered to DIO mice at a dose of 3 mg/kg twice daily for 13 weeks. Throughout the study, daily body weight and weekly food intake were monitored up to Week 4, while parameters of glucose and lipid metabolism were assessed at Week 12. Additionally, under pair-feeding conditions, DIO mice received S-309309 at the same dose regimen for 6 weeks, with daily body weight recorded. Energy expenditure was measured during the initial 7 days of treatment with S-309309, and gene expression analysis was conducted 4 days after treatment initiation

The study demonstrated that S-309309 effectively reduced food intake and attenuated body weight gain in diet-induced obese (DIO) mice throughout the duration of the research. Treatment with S-309309 also led to improvements in insulin resistance, reduced hepatic triglyceride levels, and lowered plasma alanine aminotransferase and aspartate aminotransferase levels. Additionally, gene expression associated with fibrosis was diminished. Even under pair-feeding conditions, S-309309 suppressed body weight gain, boosted energy expenditure, and upregulated intestinal gene expression linked to long-chain fatty acid beta-oxidation, suggesting its potential as a therapeutic agent for metabolic benefits in obesity.

In conclusion, the advent of this new era in obesity treatment marks a pivotal moment with the integration of pharmacotherapy combining entero-pancreatic hormones to enhance weight loss outcomes. This diverse range of effective treatments, each operating through unique mechanisms, holds the potential for tailored therapeutic strategies that address individual preferences, comorbidities, and treatment responses. By incorporating a blend of lifestyle interventions and pharmacotherapies, patients can pursue customized approaches that not only optimize health benefits but also enhance long-term quality of life. As the landscape of obesity pharmacotherapy rapidly evolves, ongoing research into their long-term clinical efficacy, safety profiles, and cost-effectiveness will continue to shape their role within comprehensive treatment plans for obesity and its associated complications in the coming years.