What ASK1 inhibitors are in clinical trials currently?

Introduction to ASK1 and Its Role

ASK1 Function and Mechanism
Apoptosis signal-regulating kinase 1 (ASK1), also known as MAP3K5, is a serine/threonine kinase that acts as an important mediator in the cellular stress response. ASK1 becomes activated in response to various stress-related stimuli such as oxidative stress (reactive oxygen species), endoplasmic reticulum stress, cytokines such as TNF-α, and toxins. Upon activation, ASK1 triggers downstream cascades—most notably the JNK and p38 mitogen-activated protein kinase pathways—thereby initiating cellular processes that involve apoptosis, inflammation, and fibrogenesis. Through its role as an upstream activator, ASK1 is capable of affecting a multitude of biological processes, including cell differentiation, survival, and death. Its unique position in the kinase network renders it a central regulator of a broad range of stress-induced cellular responses.

ASK1 in Disease Pathology
The pathological activation of ASK1 has been strongly implicated in various diseases. Elevated ASK1 activity results in inappropriate or prolonged activation of downstream kinases that can lead to tissue injury and overt pathological changes. For example, ASK1 signaling is involved in the development and progression of nonalcoholic steatohepatitis (NASH), where persistent activation leads to hepatocyte apoptosis, inflammation, and fibrosis. In addition, ASK1 has been associated with cardiovascular disorders, where its overactivation contributes to cardiac hypertrophy and remodeling. Neurodegenerative disorders, such as Huntington’s disease and amyotrophic lateral sclerosis (ALS), also demonstrate aberrant ASK1 activation, linking cellular stress with neuronal cell death. Overall, the dysregulated activity of ASK1 contributes to a crossover pathology in multiple systems—including the liver, heart, kidney, and nervous system—thus making ASK1 a promising molecular target for a range of chronic diseases.

Overview of ASK1 Inhibitors

Types of ASK1 Inhibitors
ASK1 inhibitors are chemically diverse agents developed to selectively target ASK1 kinase activity, thereby mitigating its downstream pathological signaling. The inhibitors can be broadly categorized into two types. First, ATP-competitive inhibitors bind to the kinase domain of ASK1 and directly block its enzymatic function; compounds of this type typically interact with the catalytic hinge region of ASK1, often forming hydrogen bonds with key residues such as Gln756, Val757, and Lys709. Second, allosteric inhibitors and modulators of protein–protein interactions are being explored as a way to fine-tune ASK1 activity rather than completely abolish it. The latter class is based on the concept that a delicate balance in ASK1’s activity might be preferable over total inhibition, given ASK1’s role in maintaining cellular homeostasis. Patents have been filed describing various ASK1 inhibitors of natural and synthetic origin, emphasizing the importance of discovering structurally distinct compounds that can effectively modulate ASK1 activity. These types of molecules differ in chemical structure and binding mode, offering multiple avenues for achieving therapeutic modulation of ASK1.

Mechanisms of Action
The primary mechanism of action for most ASK1 inhibitors is the competitive binding at the ATP-binding site of the kinase. This type of inhibition prevents ASK1 from phosphorylating its substrates and thereby stops the cascade that results in the activation of p38 and JNK MAPKs. Additionally, some inhibitors are designed to disrupt ASK1 dimerization or its interactions with regulatory proteins such as thioredoxin (TRX). Under normal stress conditions, TRX binds to ASK1 to prevent its activation; once oxidized, TRX dissociates, leading to ASK1 activation. An inhibitor that can either stabilize the binding of TRX or block the dimerization surface may prevent ASK1 activation altogether even in the presence of stress signals. Therefore, the design of ASK1 inhibitors involves detailed structure–activity relationship studies to optimize potency, selectivity, and pharmacokinetic profiles while minimizing off-target effects.

Current Clinical Trials of ASK1 Inhibitors

Identification of ASK1 Inhibitors in Trials
Among the ASK1 inhibitors currently in clinical trials, selonsertib stands out as the most extensively studied candidate. Developed originally by Gilead Sciences, selonsertib is an ATP-competitive inhibitor of ASK1 and has been evaluated in several clinical studies targeting a range of conditions characterized by oxidative stress and inflammation. According to multiple clinical trial records from databases such as CTGOV and WHO, selonsertib has been evaluated in patient populations with nonalcoholic steatohepatitis (NASH), severe alcoholic hepatitis (AH), diabetic kidney disease, and compensated cirrhosis due to NASH. These trials represent a spectrum of indications in which the resultant downstream inflammatory and fibrogenic signaling from ASK1 activation contributes significantly to disease pathology. In addition to selonsertib, other compounds being explored include novel chemical series derived from natural substances as described in several patents. However, based on the provided materials and the structured clinical trial entries, it is selonsertib that is most prominent and consistently reported as the ASK1 inhibitor undergoing clinical development.

Stages and Objectives of Trials
Clinical trials with selonsertib have been designed as randomized, double-blind, placebo-controlled studies. They are carried out across multiple phases with specific objectives tailored to the targeted disease state:

• In NASH: A Phase 2 study evaluated the safety and efficacy of selonsertib (in combination with other agents such as firsocostat and cilofexor) in patients with bridging fibrosis or compensated cirrhosis due to NASH. Subsequently, a Phase 3 trial aimed to assess long-term safety and efficacy regarding fibrosis improvement in adults with NASH and bridging fibrosis, utilizing changes in liver biomarkers as a key endpoint. Moreover, another Phase 3 trial conducted in India via the CTRI/WHO registry focused on the safety and efficacy of selonsertib in patients with nonalcoholic steatohepatitis with bridging fibrosis and a related trial evaluated the effectiveness of ASK1 inhibition in compensated cirrhosis due to NASH.

• In severe alcoholic hepatitis: A Phase 2, randomized, double-blind study was performed to evaluate the safety, tolerability, and efficacy of selonsertib in combination with prednisolone compared to prednisolone alone in patients with severe AH.

• In diabetic kidney disease: A Phase 2b trial (MOSAIC study) assessed selonsertib among patients with moderate to advanced diabetic kidney disease, analyzing markers of kidney function and the progression of fibrosis as outcomes.

• Pharmacokinetic and safety profiling trials: A Phase 1, open-label study was designed to evaluate the pharmacokinetics of selonsertib in subjects with normal and impaired hepatic function in order to inform dosing strategies across different patient subgroups.

Each phase has its own objectives: Phase 1 trials primarily focus on safety, tolerability, and pharmacokinetics in healthy volunteers or select patient groups; Phase 2 trials assess preliminary efficacy (and continued safety), determining appropriate dosing and initial proof-of-concept data; while Phase 3 trials are designed to confirm efficacy and further evaluate safety in a larger patient population over longer treatment durations. The endpoints measured include changes in liver fibrosis markers, improvements in liver enzymes (AST, ALT), and changes in surrogate endpoints such as imaging and histological outcomes.

Preliminary Results and Findings
The clinical data available on selonsertib have provided mixed, yet informative, results. For instance, in the Phase 2 trial related to NASH, preliminary results indicated that selonsertib as part of combination regimens could lead to improvements in liver fibrosis scores and reduction in liver enzyme levels, with the overall safety profile being acceptable. In severe alcoholic hepatitis, the combination of selonsertib with prednisolone was evaluated for its potential to reduce the inflammatory cascade and improve clinical outcomes compared to standard treatment alone. In the diabetic kidney disease study, the MOSAIC trial demonstrated that selonsertib might slow the progression of kidney dysfunction by reducing pro-fibrotic signaling; however, the endpoints and clinical significance of these changes continue to be closely scrutinized. Additionally, the pharmacokinetic study in subjects with varying hepatic function confirmed that the dosing adjustments for selonsertib can be efficiently managed across different patient cohorts.

The advanced Phase 3 studies have aimed to determine the long-term benefits and safety profile of selonsertib in fibrotic liver disease. Although some trials did not meet their primary endpoints leading to early termination in certain indications (as historically observed in the field of NASH research), the overall body of evidence still shows potential for ASK1 inhibition in modifying disease progression. The clinical trial data indicate that while direct inhibition of ASK1 can mitigate excessive inflammatory and fibrotic signaling, the heterogeneity of patient responses in terms of underlying disease mechanisms remains a challenge. Preliminary results are often nuanced, with subgroup analyses suggesting that specific patient populations may derive more clinical benefit from ASK1 inhibition than others.

Moreover, ongoing evaluations of selonsertib in different disease contexts underscore the importance of a stratified approach where biomarkers and patient selection play key roles in identifying those who may benefit the most from ASK1-targeted therapies. The current clinical trial landscape reflects a strong focus on optimizing patient outcomes in diseases where inflammation, apoptosis, and fibrosis are driven by aberrant ASK1 activity.

Implications and Future Directions

Potential Benefits of ASK1 Inhibition
ASK1 inhibitors, through their ability to disrupt a central node in the signaling pathways associated with inflammation and cellular stress, offer several potential therapeutic benefits. By effectively dampening the overactive stress response system in diseases such as NASH, diabetic kidney disease, and alcoholic hepatitis, these compounds can potentially slow disease progression and reduce the incidence of complications such as cirrhosis, heart failure, and kidney dysfunction. From a clinical perspective, targeting ASK1 has the advantage of intervening upstream in the pathological cascade, thereby potentially providing a broader effect on diverse downstream targets, including p38 and JNK, which are critical in mediating apoptosis and fibrotic processes. The benefit of ASK1 inhibition is not only confined to liver disease but also extends to neurodegenerative and cardiovascular contexts, as the pathways regulated by ASK1 are ubiquitous in stress-related tissue injury.

Challenges and Limitations
Despite the promising potential benefits, significant challenges remain in the clinical development of ASK1 inhibitors. A key limitation is the need to achieve a fine balance between ensuring sufficient inhibition to reduce pathological signaling and avoiding the complete abrogation of ASK1’s physiological roles in maintaining cellular homeostasis. Overinhibition may lead to unwanted side effects, given that ASK1 functions as an important mediator during robust physiological responses such as cellular differentiation and immune regulation. As seen in some large-scale clinical studies, adverse events related to potent inhibition of ASK1 signaling and potential off-target effects have led to difficulties in demonstrating a clear clinical benefit, particularly in heterogeneous disease populations.

Another challenge pertains to patient selection and biomarker validation. Given the multifactorial nature of diseases like NASH and diabetic kidney disease, not all patients may exhibit the same dependency on ASK1-driven pathways. As a result, robust biomarker assays are essential to identify the subpopulations that are most likely to respond to ASK1 inhibitors. The heterogeneity in trial endpoints (e.g., changes in liver fibrosis measured by imaging or histology, serum enzyme levels, or clinical outcomes) adds complexity to the interpretation of trial results, which can sometimes lead to mixed or equivocal clinical trial outcomes.

Moreover, there is the challenge of timing and exposure. Clinical trials must account for the fact that disease progression and treatment response are functions of dosage, treatment duration, and the stage of disease at which therapy is initiated. Early-phase studies have largely focused on safety and pharmacokinetics, but achieving sustained therapeutic levels over long periods while minimizing toxicity is a major hurdle in developing an effective ASK1 inhibitor.

Future Research Directions
Future research should focus on several aspects to successfully harness the potential of ASK1 inhibition. First, additional efforts in structure-based drug design and medicinal chemistry are needed to develop next-generation ASK1 inhibitors with improved selectivity, potency, and favorable pharmacokinetic properties. This may include designing compounds that target allosteric sites or modulate protein–protein interactions rather than completely inhibiting the catalytic activity, thus allowing for a more nuanced modulation of the ASK1 pathway.

Second, there is a need for better integration of biomarker research into clinical trial designs. The use of validated biomarkers will help determine which patient populations are most likely to derive benefit from ASK1 inhibition and will facilitate adaptive trial designs that can adjust participant selection and dosing regimens dynamically. This approach is crucial, especially given the variability in disease pathogenesis among patients with conditions like NASH and diabetic kidney disease. Future clinical trials may benefit from multi-center collaborations that standardize biomarker assays and endpoints to ensure consistency across studies.

Lastly, combinatorial therapies involving ASK1 inhibitors deserve further investigation. Preclinical studies suggest that simultaneous targeting of ASK1 along with other pathways implicated in disease pathology—for instance, combining ASK1 inhibitors with anti-inflammatory or antifibrotic agents—may yield synergistic benefits and overcome the limitations of monotherapy. This strategy could be particularly relevant for complex diseases where multiple cellular pathways contribute to pathogenesis. Additionally, exploring dose-escalation strategies and chronic dosing regimens in Phase 1/2 trials may provide insights into the optimal therapeutic window for ASK1 inhibitors, thereby guiding subsequent Phase 3 investigations.

Conclusion
In summary, ASK1 plays a crucial role as an upstream mediator of the stress response, linking various triggers such as oxidative stress and inflammatory cytokines to downstream pathways that culminate in apoptosis, fibrosis, and tissue injury. This central role in disease pathology makes ASK1 a promising target for therapeutic intervention across multiple disease states, including NASH, severe alcoholic hepatitis, diabetic kidney disease, and potentially various neurodegenerative and cardiovascular disorders.

Currently, the ASK1 inhibitor that is most prominent in clinical trials is selonsertib. Extensive clinical research has been undertaken to evaluate its safety, tolerability, pharmacokinetics, and efficacy across a range of indications:
• In NASH, several Phase 2 and Phase 3 studies have been conducted to assess whether selonsertib can alleviate liver fibrosis and improve liver function.
• In severe alcoholic hepatitis, combination therapy trials have been performed to compare selonsertib plus prednisolone with prednisolone alone, demonstrating an attempt to enhance treatment outcomes through modulation of inflammatory signaling.
• In diabetic kidney disease, a Phase 2b trial (MOSAIC) is investigating the compound’s effect on kidney function and fibrotic progression.
• Furthermore, Phase 1 studies have focused on pharmacokinetic assessments in different hepatic functional groups to guide dosing regimens.

While this body of work has generated promising data regarding the modulation of ASK1-dependent pathological pathways, there are also challenges to overcome. These include the need for precise patient selection, the risk of side effects from overinhibition of ASK1, and the inherent difficulty in translating surrogate biomarkers into definitive clinical outcomes. Future research must focus on optimizing the chemical properties of ASK1 inhibitors, refining clinical trial designs with robust biomarker integration, and exploring combination therapies that can leverage synergistic mechanisms to maximize patient benefit.

From a general perspective, ASK1 inhibitors represent a highly promising approach to treating a wide spectrum of diseases driven by dysregulated stress and inflammatory responses. Specific aspects of their mechanism—namely, the inhibition of downstream p38 and JNK pathways—highlight both the therapeutic benefit and the challenges associated with targeting such a pivotal signaling node. In a specific context, selonsertib stands out as the leading candidate undergoing multiple clinical trials in diverse disease settings. Its evaluation in conditions such as NASH, diabetic kidney disease, and severe alcoholic hepatitis reflects a comprehensive attempt to harness the therapeutic potential of ASK1 inhibition. Finally, from a general outlook on future implications, the ongoing clinical development, despite certain limitations and mixed results, provides valuable insights that will direct both second-generation inhibitor design and stratified patient selection strategies while fostering innovative trial methodologies.

In conclusion, the current answer to the question “What ASK1 inhibitors are in clinical trials currently?” can be primarily addressed by focusing on selonsertib, which is under investigation in several Phase 1, Phase 2, and Phase 3 clinical trials across indications like NASH, severe alcoholic hepatitis, diabetic kidney disease, and compensated cirrhosis due to NASH. The clinical trials are designed to assess safety, tolerability, pharmacokinetics, and therapeutic efficacy, with preliminary data indicating potential benefits in reducing fibrosis, inflammation, and tissue injury. However, challenges such as determining the optimal dosing regimen, the heterogeneity of disease pathophysiology, and the risk of off-target effects remain. Future research should concentrate on next-generation compounds, more robust biomarker-guided studies, and combinatory therapeutic strategies to maximize the clinical utility of ASK1 inhibition while mitigating its risks.