What FAS inhibitors are in clinical trials currently?

Introduction to Fatty Acid Synthase (FAS)
Fatty acid synthase (FAS) is a central enzyme in lipid metabolism that catalyzes the de novo synthesis of long‐chain fatty acids, most notably palmitate, using acetyl-CoA and malonyl-CoA as substrates. In normal human biology, FAS operates at low levels in most adult tissues because dietary fats provide sufficient fatty acids. However, in specific tissues—including the liver and adipose tissue—FAS activity plays a key role in maintaining cellular energy storage and membrane biogenesis, and it has major roles in regulating lipogenesis and overall energy homeostasis.

Role and Function in Human Biology
FAS is a large, multifunctional enzyme complex that is composed of several catalytic domains working in tandem. It sequentially condenses, reduces, and dehydrates intermediates to extend a growing fatty acid chain over multiple cycles. This coordinated enzymatic process not only provides the building blocks for phospholipids, sphingolipids, and triglycerides but also contributes to generating signaling molecules and lipid secondary messengers that regulate various aspects of cell signaling. FAS thereby has an indispensable role in normal cellular maintenance, proliferation, and adaptation under metabolic stress. Its activity is finely regulated by dietary factors, hormonal signals, and feedback from downstream lipid products.

Importance in Disease Pathology
In numerous pathological conditions, FAS expression and activity become dysregulated. This is particularly evident in various cancers, where FAS is markedly overexpressed compared to normal tissues. The elevated activity of FAS in cancer cells supports rapid membrane biosynthesis required for cell proliferation and facilitates resistance to apoptotic signals. Moreover, FAS-driven de novo lipogenesis can reprogram cellular metabolism, thereby assisting tumor cells in adapting to a nutrient-deficient microenvironment. Many studies have also implicated FAS overexpression as a marker of poor prognosis in malignancies such as breast, prostate, colorectal, and ovarian cancers. Apart from cancer, increased FAS activity has been linked to metabolic disorders such as obesity, non-alcoholic fatty liver disease (NAFLD), and metabolic dysfunction-associated steatohepatitis (MASH). These observations have spurred significant interest in developing selective inhibitors of FAS as potential therapeutic agents.

FAS Inhibitors
The development of FAS inhibitors has evolved over several decades as a promising strategy to target diseases where aberrant lipid biosynthesis plays a critical role. Inhibitors of FAS primarily aim to disrupt the synthesis of fatty acids in cancer cells and metabolically active tissues, thereby hindering the proliferation of tumor cells and ameliorating metabolic derangements.

Mechanism of Action
FAS inhibitors work through several mechanisms depending on the binding site and chemical nature of the inhibitor. Early inhibitors, such as cerulenin, target the ketoacyl synthase (KS) domain responsible for the condensation reaction, thereby halting chain elongation. Later inhibitors, including TVB-series compounds, have been designed to interact with multiple active sites of the enzyme with high selectivity and potency. For example, some second-generation inhibitors bind to the ketoreductase (KR) or thioesterase (TE) domains, thus interfering with the reductive and termination steps of fatty acid synthesis. By inhibiting these enzymatic functions, these drugs effectively block the production of fatty acids that cancer cells require for rapid proliferation, membrane synthesis, and signaling. The inhibition can be reversible or irreversible, and a major focus in drug development has been finding compounds that effectively inhibit FAS without eliciting off-target toxicity.

Historical Development and Milestones
Historically, the discovery of FAS inhibitors began with natural products like cerulenin and later evolved to synthetic compounds with improved pharmacokinetic profiles. Cerulenin provided initial proof-of-concept that inhibiting lipid synthesis could have antiproliferative effects; however, its broad reactivity and associated toxicities limited its therapeutic potential. Consequently, a second generation of FAS inhibitors was developed, culminating in compounds such as TVB-2640 (also known as denifanstat in certain studies). TVB-2640 has emerged as a lead candidate because of its favorable safety profile, selectivity, and oral bioavailability. It has become emblematic of the transition from non-specific, broad-spectrum inhibitors to more refined agents that target FAS in a manner compatible with clinical use. Other inhibitors targeting proteins in the de novo lipogenesis pathway, such as those aimed at acetyl-CoA carboxylase (ACC) or ATP-citrate lyase (ACLY), are also being explored; however, none have advanced as far clinically as TVB-2640.

Clinical Trials of FAS Inhibitors
The translation of FAS inhibitors from preclinical settings to clinical trials has been a gradual but notable process. Most of the current clinical studies in this area focus on TVB-2640, which represents the flagship FAS inhibitor candidate in oncology as well as in metabolic disease contexts.

Current Clinical Trials
At present, TVB-2640 is the primary FAS inhibitor that has advanced into clinical trials. It is being evaluated in various Phase II studies for its potential antitumor activity across different cancer types. For instance, TVB-2640 is undergoing evaluations in non-small cell lung cancer (NSCLC) with mutant KRAS, as well as in ovarian and breast cancers. These trials aim to assess not only the antitumor efficacy but also the tolerability, pharmacokinetics, and pharmacodynamics of the drug when administered either as a monotherapy or in combination with established chemotherapeutic agents such as paclitaxel and trastuzumab.

Beyond oncology, FAS inhibition is also being evaluated in metabolic disorders. In this context, denifanstat—a compound closely related or equivalent to TVB-2640 in terms of its FAS inhibitory action—is currently being assessed in Phase III clinical studies for the treatment of metabolic dysfunction-associated steatohepatitis (MASH). For example, one study titled “A Phase 3 Study Evaluating the Safety and Efficacy of Denifanstat in Patients With MASH and F2/F3 Fibrosis (FASCINATE-3)” is underway. Additionally, another study with a similar compound is evaluating safety and opens the opportunity to address the heavy burden of NAFLD and metabolic syndrome-related complications. These studies explore not only the biochemical modulation of FAS activity in the liver but also the resulting clinical benefits such as improvements in liver enzymes, fibrosis scores, and overall metabolic parameters.

Phases and Objectives
The clinical evaluation of FAS inhibitors has followed the traditional path of clinical development with several distinct phases, each with target objectives:

• Phase I studies focused primarily on determining safety, tolerability, pharmacokinetics, and pharmacodynamics (PK/PD) of TVB-2640. Initial dose-escalation trials are vital to determine the maximum tolerated dose (MTD) and to observe any early signs of antitumor or metabolic activity. Although many early candidates were abandoned due to toxicity or poor bioavailability, TVB-2640 has been designed to overcome these earlier obstacles.

• Phase II trials, which represent the current phase for the oncology applications of TVB-2640, are designed to evaluate its efficacy in selected cancer populations. These trials typically involve not only monotherapy arms but also combination treatment arms with standard-of-care chemotherapeutic agents. The endpoints of these studies include objective response rates, progression-free survival, and biomarker modulation (such as reductions in FAS-related products or changes in signaling pathways downstream of FAS inhibition).

• Phase III study designs are emerging particularly in the metabolic field. The FASCINATE-3 trial is one such example where denifanstat is being rigorously tested against relevant endpoints in MASH patients. The primary aims include assessing the safety and efficacy over a prolonged treatment period, improvement in surrogate markers such as liver steatosis and fibrosis, and ultimately, reduction in adverse clinical outcomes related to liver disease.

These clinical trials represent a multi-pronged strategy in which the same mechanism—FAS inhibition—is being targeted in both oncologic and metabolic disease settings. As such, the objectives vary from modulating tumor-specific growth signals to alleviating metabolic dysfunction and reducing liver fat deposition in NAFLD/MASH patients.

Implications and Future Directions
The advancement of FAS inhibitors into clinical trials has significant implications for both oncology and metabolic diseases, as well as for the broader field of targeted therapy. Although TVB-2640 currently dominates the clinical pipeline, its evolution and integration into treatment regimens could herald a new era in the management of conditions defined by excessive de novo lipogenesis.

Potential Therapeutic Applications
In oncology, the primary therapeutic application of FAS inhibitors like TVB-2640 lies in their ability to selectively target tumor cells that rely heavily on de novo fatty acid synthesis. This metabolic dependency results from the reprogramming of cancer cells and is associated with signal transduction pathways such as PI3K/AKT and ERBB-mTOR that converge on lipid synthesis. By disrupting these pathways, TVB-2640 is expected to reduce tumor proliferation, induce apoptosis, and potentially enhance the effects of conventional cytotoxic agents. Early Phase II studies have already shown promising results in patient cohorts with NSCLC, ovarian cancer, and breast cancer.

In the metabolic arena, denifanstat is being evaluated for its potential to reverse hepatic steatosis and reduce fibrosis in conditions such as non-alcoholic steatohepatitis (NASH) and metabolic dysfunction-associated steatohepatitis (MASH). Given that abnormal FAS activity contributes to excessive liver fat accumulation and fibrosis, inhibiting FAS holds promise not only in reducing lipid overload but also in restoring normal liver architecture and function. Successful outcomes in these studies could lead to new treatment options that address the heavy global burden of metabolic liver disease.

From a broader perspective, targeting FAS may also have implications in other diseases in which lipid metabolism is disrupted. For example, certain neurodegenerative disorders that have metabolic underpinnings or conditions like obesity and type 2 diabetes could eventually benefit from FAS modulation. Moreover, combination therapies that include FAS inhibitors alongside other metabolic or targeted therapies may offer synergistic effects that could overcome resistance mechanisms or potentiate the efficacy of existing treatments.

Challenges and Limitations
Despite the promising therapeutic potential, several challenges remain in the current development of FAS inhibitors. One significant challenge is the inherent difficulty in achieving high-level selectivity for FAS without off-target effects. Early-generation inhibitors, such as cerulenin, demonstrated that non-selective inhibition of FAS can lead to intolerable side effects, including gastrointestinal toxicity and anorexia. Although TVB-2640 has shown improved pharmacokinetic properties and reduced toxicity profiles, long-term safety data remain essential, especially when considering chronic diseases such as NASH where prolonged treatment periods might be required.

Another issue involves the heterogeneity of FAS expression among patients. In oncology, not all tumors exhibit uniformly high-level FAS activity, and the therapeutic response might vary depending on the metabolic profile of the tumor. Thus, patient selection and identification of predictive biomarkers become critical to maximize therapeutic benefit and minimize unnecessary exposure to potential toxicities. For metabolic indications, the baseline status of the liver and the extent of fibrosis may influence response rates, necessitating stratification of patients based on disease severity and metabolic parameters.

Furthermore, resistance mechanisms could emerge during treatment. Cancer cells, known for their metabolic flexibility, may compensate for FAS inhibition by increasing the uptake of exogenous fatty acids or upregulating alternative lipogenic pathways. This metabolic plasticity might attenuate the clinical benefit of FAS inhibitors, promoting the need for combination strategies that also target compensatory mechanisms. Similarly, in metabolic disorders, long-term inhibition of FAS must take into account the systemic metabolic ramifications, such as changes in energy expenditure and compensatory hormonal responses that could undermine therapeutic efficiency.

Future Research Directions
Looking ahead, several avenues will likely guide future research in the field of FAS inhibition. First, additional clinical studies are needed to expand the safety and efficacy data for TVB-2640 and related compounds. Larger Phase III trials, particularly in the metabolic disease realm (such as the FASCINATE-3 trial for MASH), will be critical to establish definitive therapeutic benefits and to identify any long-term adverse effects.

Second, there is an emerging need to explore combination therapy approaches. In oncology, combining TVB-2640 with other chemotherapeutics or targeted agents could help to overcome resistance mechanisms by simultaneously disrupting parallel metabolic or signaling pathways. Early preclinical evidence suggests that the combination of FAS inhibitors with inhibitors of PI3K/AKT or mTOR signaling may yield synergistic effects, thereby enhancing antitumor efficacy. Similar combination strategies may be applicable in metabolic disorders by pairing FAS inhibitors with agents that modulate insulin sensitivity or reduce inflammation.

Third, research should focus on developing robust predictive biomarkers. Such biomarkers would enable the identification of patient subsets most likely to benefit from FAS inhibition. For cancer patients, markers related to lipogenic activity, such as high levels of FAS expression or increased activity in pathways downstream of FAS (e.g., ERBB-PI3K-mTOR signaling), could serve as effective predictors of response. In metabolic diseases, biomarkers that indicate the severity of hepatic steatosis or fibrosis may help refine patient selection criteria, ensuring that those with the highest likelihood of benefit receive treatment.

Fourth, optimizing the pharmacokinetic and pharmacodynamic properties of FAS inhibitors remains a priority. Although TVB-2640 has marked significant progress over its predecessors, further chemical modifications and formulation improvements could enhance its safety profile and efficacy. Such advances might include improved bioavailability, reduced off-target interactions, and enhanced tissue specificity to minimize systemic side effects.

Lastly, the broader impact of FAS inhibition on overall metabolic homeostasis must be thoroughly investigated. Studies employing comprehensive ‘omics’ technologies, such as metabolomics and lipidomics, can provide insight into the global metabolic changes induced by FAS inhibition. These studies might reveal compensatory pathways activated upon FAS suppression and could lead to the development of second-generation inhibitors that address these metabolic feedback loops.

Conclusion
In summary, the current landscape of clinical trials for FAS inhibitors is dominated by TVB-2640, a highly selective and orally bioavailable agent that has advanced into Phase II studies for the treatment of various solid tumors—including non-small cell lung cancer, ovarian cancer, and breast cancer—and into Phase III trials for metabolic diseases such as MASH. Its mechanism of action, which involves targeting critical domains of the FAS enzyme to inhibit de novo fatty acid synthesis, underpins its therapeutic potential in conditions characterized by an abnormal reliance on lipid biosynthesis. The historical progression from early non-specific inhibitors like cerulenin through to modern agents such as TVB-2640 highlights significant milestones in the pursuit of safe and efficacious FAS inhibitors.

From an oncologic perspective, the inhibition of FAS addresses a unique metabolic vulnerability of cancer cells—their dependence on endogenous lipid synthesis—even in the presence of exogenous fatty acids. In the realm of metabolic disease, denifanstat is being evaluated to determine whether modulation of FAS activity can reverse fatty liver disease and fibrosis, thereby reducing the considerable burden of NAFLD and MASH. However, despite the promise shown by these agents, challenges remain. The potential for off-target toxicities, variability in patient response, and adaptive metabolic resistance mechanisms all underscore the need for ongoing research. Future directions include the integration of FAS inhibitors into combination regimens, the development of predictive biomarkers for patient stratification, and further refinement of drug properties to improve long-term outcomes.

Ultimately, the advancement of TVB-2640 and its clinical evaluation represent pivotal steps in harnessing the therapeutic potential of FAS inhibition. These developments offer hope for novel treatment strategies in both oncology and metabolic disorders, promising a future where the dysregulated lipid metabolism of diseases can be precisely targeted to improve patient outcomes. The future research efforts aimed at overcoming current limitations and expanding the clinical indications will be crucial in realizing the full potential of FAS inhibitors as transformative therapeutic agents.