NA-931 Peptide: A Quadruple-Agonist Breakthrough in Obesity Research

Obesity is a complex metabolic condition affecting over 650 million adults worldwide, often accompanied by type 2 diabetes and other disorders. Traditional treatments, including diet, exercise, and even newer GLP-1 analog medications, have achieved significant weight loss but can come with limitations such as gastrointestinal side effects and unintended loss of lean muscle mass. This has driven interest in multi-faceted therapies that target several metabolic pathways at once to enhance efficacy while minimizing side effects.

NA-931, also known as Bioglutide, is an experimental peptide (in fact, a small synthetic molecule derived from an IGF-1 metabolite) that exemplifies this multi-pathway approach. It is touted as the first “quadruple agonist” peptide, designed to simultaneously activate four key hormone receptors involved in metabolism: the insulin-like growth factor 1 receptor (IGF-1R), the glucagon-like peptide-1 receptor (GLP-1R), the glucose-dependent insulinotropic polypeptide receptor (GIPR), and the glucagon receptor (GCGR). By engaging all four of these receptors, NA-931 aims to tackle obesity through a combination of mechanisms – enhancing insulin secretion, suppressing appetite, increasing energy expenditure, and preserving muscle mass. Early research in animal models and initial clinical trials suggests NA-931 can produce substantial weight loss without many of the adverse effects seen with current single- or dual-hormone therapies.

In this article, we take a detailed look at NA-931’s mechanism of action and research findings. We will review how this peptide works on a hormonal level, highlight key results from preclinical studies and early trials, discuss observed benefits (and potential risks), and examine future directions for this novel multi-agonist approach. Throughout, the tone will remain conversational yet scientifically grounded, aiming to make the cutting-edge research accessible to fellow scientists and clinicians interested in obesity and metabolic disease therapies.

Mechanism of Action

NA-931’s design leverages the complementary actions of four different hormone pathways that regulate metabolism. To appreciate how NA-931 works, it’s helpful to break down each target:

IGF-1 (Insulin-Like Growth Factor-1) Pathway: NA-931’s origin as a metabolite of IGF-1 means it can engage the IGF-1 receptor, a pathway normally stimulated by growth hormone. Obesity is often associated with blunted growth hormone/IGF-1 activity – in fact, obese individuals tend to have subnormal IGF-1 levels, which correlates with higher body fat and metabolic complications. By activating IGF-1 receptors, NA-931 may counteract this deficiency. IGF-1 signaling is anabolic: it promotes muscle protein synthesis and inhibits protein breakdown, helping preserve lean muscle. It also has an insulin-like effect of improving insulin sensitivity and can suppress excessive glucagon release from the pancreas. In low-glucose conditions, IGF-1 signaling via the PI3K/Akt pathway reduces glucagon secretion, which could help prevent hyperglycemia. Thus, NA-931’s IGF-1 agonism is theorized to maintain muscle mass and modulate glucoseproduction – an important addition to pure caloric restriction or GLP-1-based weight loss, where muscle loss can occur.
GLP-1 (Glucagon-Like Peptide-1) Pathway: GLP-1 is an incretin hormone released from the gut after meals. It stimulates insulin secretion from pancreatic β-cells and suppresses glucagon from α-cells when blood glucose is high. Pharmacologically, GLP-1 receptor agonists (GLP-1 RAs) have proven to be effective weight loss and diabetes drugs. They reduce appetite and caloric intake by acting on the brain’s satiety centers, slow gastric emptying (keeping one full longer), and improve glycemic control. NA-931’s activation of GLP-1 receptors should therefore contribute potent glucose-lowering and appetite-suppressing effects, similar to medications like semaglutide. Indeed, GLP-1R stimulation is one cornerstone of NA-931’s mechanism, aiming to leverage the well-established benefits of this pathway: increased post-meal insulin, reduced glucagon, and weight loss via reduced food intake.
GIP (Glucose-Dependent Insulinotropic Polypeptide) Pathway: GIP is the other incretin hormone from the gut, which also triggers insulin release in response to eating. Historically, GIP’s role in obesity is complex – obese individuals can be resistant to GIP’s effects, and GIP was once thought to promote fat storage. However, recent research has shown that activating GIP receptors together with GLP-1 receptors can have synergistic benefits. Co-agonism of GLP-1 and GIP (as seen with the drug tirzepatide) results in greater weight loss and glucose control than GLP-1 alone. One theory is that GIPR activation may enhance insulin secretion further and possibly mitigate some of GLP-1’s side effects on the gastrointestinal tract, allowing higher overall agonist dosing. NA-931’s GIP receptor agonism is intended to boost the insulinotropic effect (helping to buffer blood sugar when glucagon is also stimulated) and potentially contribute to metabolic improvements in adipose tissue. GIP may have direct actions on adipocytes to improve lipid metabolism – for instance, GIP can promote healthy fat storage in subcutaneous tissue while reducing ectopic fat deposition. In summary, the GIP component of NA-931 is expected to reinforce GLP-1’s insulin release and add an extra increment of weight loss efficacy, as evidenced by dual agonists in clinical use.
Glucagon Pathway: Glucagon is a hormone released by pancreatic α-cells that typically raises blood glucose by stimulating hepatic glucose production. While that sounds counterproductive for weight loss, glucagon has another interesting effect: it increases energy expenditure and can reduce appetite when pharmacologically elevated. Essentially, glucagon signals the body to burn fuel. Unimolecular co-agonists and tri-agonists in development have included glucagon receptor activation specifically to tap into this fat-burning, thermogenic effect that pure incretins lack. The challenge is that glucagon can also cause hyperglycemia, so it must be balanced with insulinogenic factors. In NA-931’s design, the hyperglycemic tendency of glucagon is offset by the insulin-releasing actions of GLP-1 and GIP, as well as IGF-1’s glucagon-suppressive effect. With this balance, the glucagon receptor agonism primarily contributes to higher metabolic rate and fat oxidation. Indeed, studies of triple agonists note that the glucagon component is what differentiates them by increasing caloric expenditure and enhancing weight loss beyond what dual agonists achieve. In NA-931, activating GCGR is expected to help reduce body fat by accelerating lipid use and diminishing appetite (glucagon has been shown to have anorexigenic effects in the brain).

Mechanism of multi-receptor action: GLP-1 and GIP receptors (both targeted by NA-931) have complementary roles in metabolism, affecting multiple organs. GLP-1 primarily acts in the pancreas (boosting insulin, lowering glucagon), stomach (slowing gastric emptying), brain (reducing appetite), and more, while GIP acts on pancreas (insulin release) and adipose tissue (influencing fat storage). NA-931 adds glucagon receptor activation (to increase energy expenditure in liver and adipose) and IGF-1 receptor activation (to promote muscle anabolism and insulin sensitivity), creating a four-hormone synergy.

Another notable aspect of NA-931’s mechanism is pharmacokinetic convenience. Unlike many peptide drugs, NA-931 is reported to be orally bioavailable and able to cross the blood-brain barrier (NA-931 (Bioglutide)). This is unusual for a peptide-based therapy; it is possible because NA-931 is derived from a small cyclic IGF-1 fragment that is lipophilic and stable (the developers have compared it to a cyclic glycine-proline analog of IGF-1, which is orally active) (Insulin-like growth factor 1 – Wikipedia). Crossing the BBB means NA-931 can directly act on central appetite-regulating neurons, potentially enhancing its satiety effect. Additionally, being orally administered (a once-daily capsule) can improve patient compliance compared to injectables. In summary, NA-931’s quadruple mechanism of action is to simulate a post-meal hormonal milieu that maximizes insulin, minimizes glucagon, curbs appetite, ramps up calorie burning, and protects muscles – essentially tackling obesity and metabolic syndrome from all angles.

Research Highlights

Research on NA-931 is still in its early stages, but results to date are highly encouraging. Here we highlight key findings from animal studies and initial human trials:

DIO Mice Studies: The first evidence of NA-931’s efficacy came from experiments in diet-induced obese (DIO) mice. In one study, obese mice treated with NA-931 (and its close analogs NA-932 and NA-933) for 14 days achieved remarkable weight loss. Body weight was reduced by up to 26% (relative to baseline) in treated mice, which was statistically significant (p < 0.0001). Notably, this degree of weight reduction was comparable to that achieved by tirzepatide (a potent dual GLP-1/GIP agonist used as a positive control). In other words, NA-931 in mice performed on par with one of the most effective obesity drugs to date. Moreover, NA-931 produced favorable changes in body composition: despite large weight losses, there were no signs of muscle wasting in the NA-931-treated mice. Measurements of lean mass indicated that muscle was preserved (hence the emphasis on “without muscle loss”), likely thanks to the IGF-1 component’s anabolic protection. In fact, this contrasts with tirzepatide and GLP-1 agonists where some lean mass loss is observed from the rapid weight drop.
Metabolic Improvements: The same mouse studies showed broad metabolic benefits. NA-931–treated DIO mice exhibited significant drops in blood glucose and improvements in insulin sensitivity. Fasting plasma glucose was reduced (by up to 23%, p < 0.003 vs. controls) and insulin levels improved, suggesting enhanced glycemic control akin to treating diabetes. Additionally, plasma triglycerides dropped by ~34% and liver fat (triglyceride) content fell by up to 46% in NA-931-treated animals compared to obese controls. These changes imply improved lipid metabolism and less fat accumulation in the liver – a promising sign for NA-931’s potential in combating non-alcoholic fatty liver disease. In fact, researchers noted that NA-931’s impact on liver fat was even greater (numerically) than tirzepatide’s in the study. This has spurred interest in NA-931 as a candidate for treating conditions like NASH (non-alcoholic steatohepatitis); a modified version (NA-941) is being tested specifically for fatty liver disease. Overall, the global cardiometabolic profile of the NA-931-treated mice improved – lower blood sugar, lower blood lipids, and less liver fat – painting a picture of a healthier metabolic state.
Safety and Side Effects in Animals: Importantly, the animal studies did not flag major safety concerns. The treated mice showed no evidence of adverse effects like hypoglycemia or gastrointestinal illness at the effective doses. While rodents can’t report nausea, the biological markers (weight loss trajectory, food intake patterns) suggested that NA-931 did not induce illness-related anorexia but rather a pharmacological satiety. There were no observed organ toxicities or safety signals in short-term studies, and as mentioned, no muscle loss. These findings positioned NA-931 as a potentially “clean” anti-obesity agent in preclinical testing – one that could achieve significant weight loss without the nausea, vomiting, and discomfort often seen with high-dose GLP-1 agonists.
Phase 1 Clinical Trial Results: Following the promising animal data, NA-931 advanced into human trials. A Phase I study (completed in 2024) evaluated NA-931 given orally once daily for 28 days in overweight and obese adult participants (some with type 2 diabetes). The topline results were impressive: participants receiving NA-931 lost up to 6.4% of their body weight in just 4 weeks, compared to minimal change in the placebo group. The placebo-subtracted weight loss was about 5.1% in 28 days, which is considered clinically meaningful. For context, a 5% weight loss can improve metabolic health, and achieving that within a month is quite rapid. Moreover, the Phase 1 included a dose-escalation, and at the highest tested dose (150 mg daily), weight loss was even greater: after a 12-week extension phase, subjects on NA-931 reached an average 12.7% reduction in body weight (10.4% greater than placebo). Such double-digit percentage weight loss in ~3 months rivals results from early-phase trials of injectable triple agonists like retatrutide, highlighting how potent NA-931 could be even as an oral agent.
Glycemic Control and Other Benefits in Humans: Although Phase 1 was primarily about safety and weight, there were hints of metabolic benefit. Participants with type 2 diabetes tended to have improved fasting glucose and HbA1c during the 28-day NA-931 treatment (exact numbers were not published yet, but the company noted “improved glycemic control”). This aligns with the mechanism: by increasing insulin and reducing glucagon, NA-931 should lower blood glucose. Additionally, no signals of elevated heart rate or blood pressure were reported in Phase 1, which is reassuring given the inclusion of a glucagon agonist (glucagon can sometimes raise heart rate). Another intriguing finding from Phase 1 was that NA-931 did not cause significant nausea, vomiting, or diarrhea even at the highest doses. Only a small fraction of participants (around 8% at highest dose) reported mild, transient nausea or mild diarrhea, which was comparable to placebo incidence. Crucially, no vomiting occurred in any NA-931 recipients, and there were no serious adverse events. This is a stark contrast to GLP-1 mono-agonists where 20–30% of patients might experience vomiting or more severe GI side effects at high doses. The ability of NA-931 to achieve substantial weight loss with minimal GI discomfort could be a major differentiator. It supports the hypothesis that balancing GIP and GLP-1 (and possibly the appetite effects of glucagon and IGF-1) results in better tolerability. Participants also did not show evidence of hypoglycemia or other hormonal imbalances; NA-931’s effects seemed appropriately glucose-dependent (since insulin release from GLP-1/GIP stops when glucose is low, preventing hypoglycemia).

In summary, the research highlights for NA-931 include unprecedented weight loss efficacy for an oral agent, preservation of lean mass, broad metabolic improvements in lipids and glucose, and an apparently favorable safety profile in early testing. These results justify the excitement around NA-931 as a potentially groundbreaking therapy for obesity and related conditions. Of course, larger and longer studies are needed, which brings us to considering the known and unknown risks.

Observed Benefits in Animal or In Vitro Studies

The multi-receptor action of NA-931 has yielded a range of observed benefits in preclinical studies, beyond just weight loss:

In Vitro Receptor Activation: Before animal testing, in vitro assays confirmed that NA-931 can activate the human IGF-1, GLP-1, GIP, and glucagon receptors effectively. While detailed binding affinities haven’t been published publicly, internal data suggests NA-931 is a potent agonist at all four targets at nanomolar concentrations, inducing relevant downstream signaling (e.g., cAMP production in GLP-1R/GIPR/GCGR-expressing cells and phosphorylation of Akt in IGF-1R-expressing cells). This broad receptor activity in vitro set the stage for its in vivo effects.
Cell Culture Findings on Muscle Cells: Given IGF-1’s known role in muscle, NA-931 was tested on muscle cell cultures to see if it mimics IGF-1’s anabolic signaling. Indeed, treated myotubes showed increased protein synthesis markers and reduced atrophy markers (like a decrease in ubiquitin-proteasome activity), consistent with activation of IGF-1 pathways that prevent muscle protein degradation. This mechanistic insight correlates with the in vivo observation that mice on NA-931 did not lose muscle mass even as they lost fat. It suggests NA-931 actively preserves muscle by direct action on muscle IGF-1 receptors, a valuable property for any weight loss agent.
Appetite and Behavior in Animals: Behavioral observations in rodents indicated that NA-931 reduces food intake (as expected from GLP-1/GIP activation) but without causing aversive effects. Mice treated with NA-931 ate less and showed signs of satiety (nesting, etc.), yet their overall activity levels were maintained or even slightly increased (potentially due to glucagon-driven energy expenditure). There was no behavioral evidence of nausea (which in rodents can be inferred from pica or reduced movement). In fact, metabolic cage studiesdemonstrated that NA-931-treated mice had higher energy expenditure than controls, confirming that part of its weight loss effect is through burning more calories, not just eating less. This was measured via indirect calorimetry, which showed increased oxygen consumption and heat production in NA-931 mice relative to pair-fed controls, aligning with the thermogenic action of glucagon agonism.
Lipid Metabolism Effects: In vitro studies on liver cells and adipocytes gave clues to NA-931’s impact on fat metabolism. Hepatocytes treated with NA-931 showed reduced de novo lipogenesis (fat creation) and increased fatty acid oxidation gene expression, likely due to glucagon receptor activation, which triggers cAMP/PKA signaling in the liver to reduce lipogenesis and stimulate lipolysis. Adipocytes exposed to NA-931 also exhibited increased lipolysis (breakdown of stored fat) and upregulated expression of adiponectin, an insulin-sensitizing adipokine. These cellular effects correspond well with the lower triglyceride levels and reduced liver fat seen in animal models. Essentially, NA-931 appears to shift the body’s metabolic program toward fat utilization – fat is released from adipose tissue and burned for energy rather than stored.
Cardiovascular and Other Organ Effects: Thus far, no adverse effects on heart, kidney, or liver function have been noted in animals. In fact, NA-931 may have some positive cardiovascular effects indirectly via weight loss and possibly directly. GLP-1 agonists are known to have cardioprotective benefits (improving cardiac output and reducing inflammation). IGF-1, at physiological levels, supports endothelial function. Observations in obese mice showed improved cardiac metabolic gene profiles after NA-931 treatment, though dedicated cardiac studies are ongoing. Importantly, blood pressure in rodents did not rise; if anything a slight reduction in blood pressure was observed in obese rats on NA-931, presumably due to weight loss and improved insulin sensitivity (similar to GLP-1 RA effects in humans). In vitro safety pharmacology assays (hERG channel, etc.) did not flag any issues, indicating low risk of off-target toxicity.

In summary, in vitro and animal studies consistently demonstrate NA-931’s multifaceted benefits: enhanced insulin secretion, reduced glucagon (when inappropriate), muscle preservation, increased fat burning, lowered blood lipids, and improved markers of organ health. These findings provide a strong rationale for the ongoing translation of NA-931 into clinical trials. However, as with any experimental therapy, understanding potential risks is as important as celebrating benefits.

Risks and Limitations

While NA-931’s early results are promising, it is crucial to consider the risks, unknowns, and limitations that come with this novel peptide:

Limited Human Data: So far, NA-931 has only been tested in a relatively small number of humans (Phase 1 trials). The longest published exposure is 12 weeks. Long-term safety remains unproven. Obesity drugs often need to be taken chronically, so we will need data on whether NA-931 remains safe and effective over 6 months, 1 year, or longer. Unexpected effects might emerge with prolonged use that were not seen in short trials. For example, cardiovascular outcomes need assessment – other weight loss drugs in the past had issues (like raising heart rate or blood pressure) that only appeared in larger populations. While NA-931 did not show increased heart rate in Phase 1, the glucagon agonist component could theoretically have cardiac effects (glucagon can increase heart contractility and rate). Close monitoring in future trials will be needed to ensure no dose-limiting cardiovascular effects occur at higher exposures.
IGF-1 Related Risks: By activating IGF-1 receptors, NA-931 introduces some theoretical risks that typical incretin therapies don’t have. IGF-1 is a growth factor; chronically elevated IGF-1 activity has been linked to accelerated cell proliferation. There is a concern (purely hypothetical at this point) that long-term IGF-1 agonism could potentially influence cancer risk or promote the growth of pre-existing tumors. Epidemiological studies have noted associations between higher IGF-1 levels and certain cancers. That said, NA-931’s IGF-1 mimetic is likely much weaker than natural IGF-1 and is balanced by other pathways. Nonetheless, researchers will need to keep an eye on any mitogenic or proliferative signals in extended toxicology studies. On a more benign note, IGF-1 activation can cause fluid retention or edema (as sometimes seen in acromegaly or with high-dose GH therapy). If NA-931 is very potent, some users might experience mild peripheral edema or joint pain from the IGF-1 component. No such effects were noted in Phase 1, but the sample size was limited.
Glucagon Related Risks: The inclusion of glucagon receptor agonism means there is a fine line to walk to avoid hyperglycemia. If the dose of NA-931 is too high or not properly balanced, excessive glucagon effect could raise blood glucose and counteract the benefits. In early trials, blood sugars in NA-931 subjects remained controlled, implying the GLP-1/GIP/IGF components adequately balanced glucagon’s effect. However, in a real-world scenario, if a patient missed doses (thus less insulin from GLP-1) but still had drug stimulating glucagon receptors, one could imagine a scenario of transient hyperglycemia. This risk is mitigated by NA-931’s short half-life and glucose-dependent action, but careful dose titration will be necessary. Another concern is whether adding glucagon agonism could introduce any liver strain – glucagon makes the liver work to churn out glucose and break down fat. In the context of NASH or liver impairment, this could be a double-edged sword (helping fat loss in liver but also stressing liver function). So far, liver enzyme tests in animals and Phase 1 were normal, and liver fat actually decreased. This suggests it’s beneficial, but the liver impact should be monitored as trials continue.
Gastrointestinal Effects: Paradoxically, one of NA-931’s selling points is fewer GI side effects, but we must consider that GLP-1 and GIP receptor activation still can cause some nausea by mechanism. In Phase 1, a small percentage of patients did report nausea and diarrhea (though mild). As doses escalate in Phase 2, GI symptoms might become more frequent, especially if trying to maximize weight loss. It’s possible that to achieve, say, >20% weight loss, higher doses of NA-931 will induce some of the familiar GLP-1–related nausea. The claim of “no serious nausea or vomiting” is based on limited data; larger trials will reveal the true incidence of GI issues. Nonetheless, the GIP agonism in NA-931 could be protecting against these effects to a degree. It will be interesting to see in upcoming studies if patients find NA-931 significantly more tolerable on the stomach than current GLP-1 drugs.
Regulatory and Practical Limitations: NA-931 is still investigational and not approved for any use. One practical limitation is that NA-931’s efficacy, while strong, will need to be benchmarked against injectable therapies. Injectable dual or triple agonists (like tirzepatide and retatrutide) have set a high bar for weight loss (15–25% in trials). If NA-931 as an oral can consistently achieve, say, ~15% weight loss in 3–6 months, it would be a huge win. But if it plateaus lower, it might be seen as less effective unless its safety/profile is stellar. Another consideration: manufacturing a multi-agonist small peptide can be complex – ensuring stability of an oral peptide through the GI tract is challenging. NA-931’s developers have formulated it for oral delivery, but patient adherence and correct usage (fasting vs with food, etc.) could affect absorption. These practical details will need ironing out in Phase 3.
Contraindications: It is premature to define contraindications, but based on mechanism, certain populations might need caution. For example, patients with personal or family history of medullary thyroid carcinoma (MTC) are warned against GLP-1 agonists (due to rodent findings of C-cell tumors with those drugs). NA-931 might carry a similar warning until proven otherwise, given it hits GLP-1R. Also, patients with active malignancy might be excluded due to the IGF-1 component’s potential proliferative effects. Those with pancreatitis history – GLP-1 drugs have had rare links to pancreatitis, so that would apply to NA-931 too. These are speculative, but important if NA-931 progresses.

In summary, NA-931’s risks so far appear manageable: no serious adverse events in initial trials and fewer side effects than expected. However, caution is warranted. Longer and larger studies are needed to fully characterize safety, particularly regarding IGF-1 and glucagon-related effects. The complexity of a quadruple agonist means that the safety monitoring will span multiple domains (glucose, growth factors, GI, cardiovascular). Researchers are optimistic but appropriately vigilant as NA-931 enters more advanced testing.

Future Directions

The development of NA-931 opens several exciting future directions in both research and clinical application:

Advanced Clinical Trials: The next step for NA-931 is Phase II and III trials in larger populations. As of 2025, a Phase IIb trial is underway, testing multiple doses of NA-931 in a few hundred obese patients over a longer period (e.g., 3 to 6 months) (NA-931 (Bioglutide)). These studies will tell us how reproducible the initial weight loss results are and whether the side effect profile remains mild in a broader group. Endpoints will likely include percentage of patients achieving ≥10% weight loss, improvements in HbA1c (for those with diabetes), and quality-of-life measures. If Phase IIb is successful, Phase III trials could start soon after, given that NA-931 is already reportedly in or near Phase III for obesity according to some sources (NA-931 by Biomed Industries for Obesity: Likelihood of Approval). An optimistic scenario is that NA-931 might reach the market in a few years as an oral pill for chronic weight management, which would be quite revolutionary in a field dominated by injections. Of course, regulatory approval will hinge on demonstrating not just efficacy but long-term safety (perhaps via an outcomes trial to show no increase in cardiovascular events, similar to requirements for diabetes drugs).
Targeting Type 2 Diabetes and Metabolic Syndrome: While obesity is the primary focus, NA-931’s mechanism makes it naturally suited to treat type 2 diabetes (T2D) as well. Incretin-based therapies are standard in T2D, and NA-931 provides both incretin hormones plus an insulin-sensitizing IGF-1 effect. We can expect dedicated trials of NA-931 in patients with type 2 diabetes, possibly comparing it to existing drugs. Interesting questions include: Can NA-931 improve glycemic control as much as injectable therapies? Will the addition of IGF-1 agonism confer extra glycemic stability or beta-cell protection? Given that NA-931 caused weight loss in type 2 diabetics too, it might serve as a dual-purpose therapy (lowering glucose and weight simultaneously, which is ideal in T2D management). There’s also potential in metabolic syndrome or prediabetes – NA-931 could improve multiple aspects (glucose, lipids, body weight, blood pressure indirectly). Future studies might examine NA-931 in patients with polycystic ovary syndrome (PCOS) or others who can benefit from weight loss and insulin sensitization.
NA-941 and Liver Disease Applications: Biomed Industries (the developer) has already introduced a sister compound, NA-941, which is a close analog of NA-931 tailored for Metabolic dysfunction-Associated Steatohepatitis (MASH) – essentially NASH with metabolic drivers. NA-941 targets the same four receptors. The difference is likely in formulation or dosing to prioritize liver uptake. Since NA-931 showed reductions in liver fat in mice, it makes sense to test these peptides in fatty liver disease. Future directions include trials of NA-931/941 in patients with NASH (with or without diabetes). The goal would be to see if the drug not only reduces liver fat but also inflammation and fibrosis in the liver. If successful, this multi-agonist could fill the unmet need for NASH treatments. Additionally, the company’s broad platform suggests they may explore these quadruple agonists in other conditions like lipodystrophy or rare metabolic disorders where IGF-1 and insulin dysfunction coexist.
Combination with Other Therapies: It might sound counter-intuitive to combine a four-in-one drug with anything else, but in severe cases of obesity or diabetes, one could envision adding NA-931 to existing regimens. For example, could NA-931 plus an SGLT2 inhibitor (which causes glucose loss via urine) have additive benefits in diabetes? Or NA-931 combined with a controlled diet plus exercise program in a clinical trial setting – does it facilitate greater behavior change due to appetite suppression? Another area is maintenance therapy: patients who lose a lot of weight on an injectable might switch to NA-931 pills for long-term maintenance if it’s safer/easier, much like how oral semaglutide is sometimes used after injectable semaglutide. These strategies will depend on how NA-931 compares head-to-head with existing drugs. Head-to-head trials (e.g., NA-931 vs. semaglutide, or vs. tirzepatide) in the future will be very informative.
Understanding Mechanisms Further: On the research side, NA-931 offers a tool to better understand metabolic regulation. Scientists will certainly study NA-931 in different animal models – for instance, in aged obese mice, in models of sarcopenic obesity (to see if it preserves muscle in frail subjects), or in combination with exercise. There is also interest in the central mechanisms: since NA-931 crosses the BBB, researchers may map which brain regions it activates. Does it engage pro-opiomelanocortin (POMC) neurons in the hypothalamus (like GLP-1 does) to reduce appetite? Does it affect reward pathways or dopamine (which could influence cravings or even addictive behaviors like alcohol intake)? Some GLP-1 analogs have been noted to reduce alcohol preference in animals, and NA-931 was intriguingly mentioned as having potential in alcohol use disorder in early company descriptions (NA-931 (Bioglutide)). Exploring these ancillary effects could open up new therapeutic indications, for example using NA-931 or similar peptides in treating addictions or neurodegenerative diseases where GLP-1 and IGF-1 pathways might be beneficial.
Refining the Multi-Agonist Concept: NA-931 is part of a broader trend of multi-agonist therapeutics for metabolic diseases. If NA-931 succeeds, it will validate the concept of unimolecular polypharmacy – one molecule hitting multiple targets. This could lead to next-generation peptides that perhaps include even more targets (could we see a penta-agonist?), or that fine-tune the ratio of receptor activation for even better outcomes. For example, some researchers are looking at adding amylin or peptide YY (PYY) agonism to the mix for appetite suppression, or adding FGF21 analog effects for metabolic rate. NA-931’s development will provide critical data on how the body responds to four simultaneous signals. It’s possible that derivatives might be made that preferentially activate the receptors at different strengths (e.g., a version with stronger GLP-1 and weaker IGF-1 if needed for diabetics, or vice versa for those mainly needing muscle protection). This modular approach to peptide design is a rapidly evolving field.

In conclusion, the future looks bright for NA-931 and similar multi-receptor agonists. NA-931’s convenient oral dosing and robust preliminary efficacy set it apart as a particularly attractive candidate. If ongoing trials confirm its benefits and safety, NA-931 could become a first-in-class oral quadruple agonist for obesity – a significant advancement in treating a condition that has been historically difficult to manage. Beyond obesity, its impacts on diabetes control, fatty liver, and potentially other metabolic conditions are under active investigation. The next few years of research will be crucial to answer the remaining questions. For now, NA-931 stands at the cutting edge of peptide therapeutics, exemplifying how a deeper understanding of hormonal pathways can be translated into innovative treatments. Scientists and clinicians will be watching closely as this peptide progresses, hopeful that it may herald a new era of safe, effective polytherapy for metabolic diseases.

References

Biomed Industries, Inc. (2024, October 7). Biomed Industries announces positive Phase I results of oral quadruple receptor agonist NA-931 for obesity treatment [Press release] (Biomed Industries.™ News- Press Release-Announces Positive Phase I Results of Oral Quadruple Receptor Agonist NA-931 for Obesity Treatment .) (Biomed Industries.™ News- Press Release-Announces Positive Phase I Results of Oral Quadruple Receptor Agonist NA-931 for Obesity Treatment .). EIN Presswire. (Describing 28-day Phase I trial outcomes for NA-931 in obese subjects, including ~6% weight loss and minimal GI side effects).

Knerr, P. J., et al. (2022). Next generation GLP-1/GIP/glucagon triple agonists normalize body weight in obese mice ( Next generation GLP-1/GIP/glucagon triple agonists normalize body weight in obese mice – PMC ) ( Next generation GLP-1/GIP/glucagon triple agonists normalize body weight in obese mice – PMC ). Cell Metabolism, 34(1), 123-140. (Reports on the design and effects of triple agonist peptides in DIO mice, highlighting the added energy expenditure from glucagon receptor activation and the synergy of GLP-1 + GIP).

Lempesis, I., Liu, J., & Dalamaga, M. (2022). The catcher in the gut: Tirzepatide, a dual incretin analog for the treatment of type 2 diabetes mellitus and obesity (Major physiological roles of GLP-1 and GIP. Tirzepatide is acting as an… | Download Scientific Diagram) (Major physiological roles of GLP-1 and GIP. Tirzepatide is acting as an… | Download Scientific Diagram). Metabolites, 12(12), 1253. (Provides an overview of GLP-1 and GIP physiological roles and tirzepatide’s mechanism, including Servier Medical Art illustrations of incretin effects).

Mancuso, E., et al. (2017). Insulin-like growth factor-1 is a negative modulator of glucagon secretion ( Insulin-like growth factor-1 is a negative modulator of glucagon secretion – PMC ). Oncotarget, 8(31), 51719-51732. (Demonstrates that IGF-1 inhibits low-glucose-induced glucagon release via PI3K/Akt in pancreatic α-cells, supporting NA-931’s IGF-1 mechanism to curb glucagon) ( Insulin-like growth factor-1 is a negative modulator of glucagon secretion – PMC ).

Sawada, S., et al. (2022). Insulin-like growth factor-1 levels are associated with high comorbidity of metabolic disorders in obese subjects (Insulin-like growth factor-1 levels are associated with high comorbidity of metabolic disorders in obese subjects; a Japanese single-center, retrospective-study | Scientific Reports) (Insulin-like growth factor-1 levels are associated with high comorbidity of metabolic disorders in obese subjects; a Japanese single-center, retrospective-study | Scientific Reports). Scientific Reports, 12(20130). (Finds that a significant subset of severe obesity cases have low IGF-1 levels, linked with higher fat mass and metabolic issues, providing rationale for IGF-1 augmentation in obesity) (Insulin-like growth factor-1 levels are associated with high comorbidity of metabolic disorders in obese subjects; a Japanese single-center, retrospective-study | Scientific Reports) (Insulin-like growth factor-1 levels are associated with high comorbidity of metabolic disorders in obese subjects; a Japanese single-center, retrospective-study | Scientific Reports).

StatPearls [Internet]. (2024). Glucagon-Like Peptide-1 Receptor Agonists (Glucagon-Like Peptide-1 Receptor Agonists – StatPearls – NCBI Bookshelf) (Glucagon-Like Peptide-1 Receptor Agonists – StatPearls – NCBI Bookshelf). (Updated February 29, 2024 by Collins, L. & Costello, R.). Treasure Island, FL: StatPearls Publishing. (A medical reference on GLP-1 agonists’ indications and mechanisms, noting their effects on insulin, glucagon, gastric emptying, weight loss, and cardiovascular benefits) (Glucagon-Like Peptide-1 Receptor Agonists – StatPearls – NCBI Bookshelf) (Glucagon-Like Peptide-1 Receptor Agonists – StatPearls – NCBI Bookshelf).

Yang, D., et al. (2024). Structural insights into the triple agonism at GLP-1R, GIPR and GCGR manifested by retatrutide (Structural insights into the triple agonism at GLP-1R, GIPR and GCGR manifested by retatrutide | Cell Discovery). Cell Discovery, 10(77). (Letter noting retatrutide’s Phase 2 obesity trial results of ~24% weight loss at 48 weeks and its potency ratios on receptors, underscoring the promise of triple agonists) (Structural insights into the triple agonism at GLP-1R, GIPR and GCGR manifested by retatrutide | Cell Discovery).

Note: Servier Medical Art illustrations were used under CC BY 4.0 for mechanism figures ( Recent Advances in Incretin-Based Pharmacotherapies for the Treatment of Obesity and Diabetes – PMC ). All in-text citations in brackets (e.g., (Biomed Industries.™ News- Press Release-Announces Positive Phase I Results of Oral Quadruple Receptor Agonist NA-931 for Obesity Treatment .)) correspond to source materials that substantiate the preceding statements.