What clinical trials have been conducted for Elafibranor?

Elafibranor is an investigational, orally administered, dual peroxisome proliferator‐activated receptor (PPAR) α/δ agonist that has been the subject of extensive clinical research. It is being evaluated across multiple indications, predominantly within the realm of cholestatic and metabolic liver diseases such as Primary Biliary Cholangitis (PBC), Primary Sclerosing Cholangitis (PSC), and Nonalcoholic Steatohepatitis (NASH). The clinical development program for Elafibranor encompasses a broad spectrum of studies designed to assess its safety, pharmacokinetics (PK), pharmacodynamics (PD), therapeutic efficacy, and tolerability in various subpopulations including healthy volunteers, pediatric patients, and those with specific organ impairments.

Elafibranor’s mechanism of action is centered on its ability to activate both the PPARα and PPARδ receptors. This dual agonist activity is thought to target several pathophysiological processes simultaneously. Activation of PPARα primarily influences lipid metabolism, while PPARδ activation modulates inflammation and energy homeostasis. Together, these pharmacologic effects may reduce steatosis, inflammation, and fibrosis in the liver—a key therapeutic goal in diseases such as NASH and PBC. The chemical profile of Elafibranor shows promising oral bioavailability, and its safety profile has been further characterized through dedicated phase I studies examining drug–drug interactions, the effect of food on circulation levels, and altered pharmacokinetics in special populations like the elderly, pediatric patients, and those with hepatic or renal impairments.

The clinical development of Elafibranor primarily targets liver-related diseases where metabolic dysregulation, inflammation, and fibrotic processes play a central role. Key therapeutic indications under investigation include:
- Nonalcoholic Steatohepatitis (NASH): Owing to the fact that NASH is frequently associated with metabolic syndrome and insulin resistance, Elafibranor is studied for its potential to resolve hepatic steatosis and inflammation while mitigating fibrosis.
- Primary Biliary Cholangitis (PBC): PBC, an autoimmune cholestatic liver disease, represents another critical indication. Multiple trials have been conducted to assess the efficacy of Elafibranor, particularly in patients with inadequate response or intolerance to the current standard of care, ursodeoxycholic acid (UDCA).
- Primary Sclerosing Cholangitis (PSC): In addition to PBC, Elafibranor is also evaluated for PSC, another cholestatic condition, aiming to establish a broader role in the management of cholestatic liver diseases.

This versatility in therapeutic applications reflects the drug’s design to modulate several underlying pathways, which is a critical aspect of its clinical development journey.

Clinical trials are the cornerstone of the drug development process. In the context of Elafibranor, a series of studies have been structured to gather robust data on safety, efficacy, pharmacokinetic/pharmacodynamic behavior, and tolerability across various patient populations and conditions.

The clinical development of Elafibranor has encompassed all conventional phases of a clinical trial:
- Phase I: These early-stage studies are primarily conducted in healthy volunteers to evaluate the basic pharmacokinetics and safety profile of Elafibranor. For example, multiple phase I studies were designed to assess the effects of food on drug bioavailability, drug–drug interactions (notably with indomethacin), and PK parameters in populations such as elderly adults and patients with organ impairments.
- Phase II: These studies begin to evaluate the therapeutic efficacy of Elafibranor in patients with the target diseases, while continuing to monitor safety. Phase II trials are frequently randomized, double-blind, and placebo-controlled. Studies in populations with NASH and PBC fall within this phase, often including additional subgroup and biomarker analyses to fine-tune patient selection criteria.
- Phase III: At this stage, larger controlled trials are conducted to robustly evaluate the safety and efficacy of Elafibranor in a broader population. Phase III studies have been critical for establishing clinical endpoints such as biochemical response markers, improvements in liver histology, and patient-reported outcomes in conditions such as NASH and PBC.
- Phase IIIb and Expansion Studies: These are rigorous studies that focus on reinforcing Phase III findings, often including continued assessments after regulatory submission has been initiated, as seen in certain PBC trials.

The successful conduct of clinical trials for Elafibranor has required adherence to strict regulatory guidelines. These regulations ensure that:
- Data Integrity and Patient Safety: Design, conduct, and reporting are in compliance with guidelines from regulatory authorities (e.g., FDA, EMA), ensuring the protection of patients and the integrity of the data.
- Good Clinical Practice (GCP): All investigations, from phase I through phase III, are performed following internationally recognized standards that facilitate reliable data collection, robust statistical analyses, and ethical participant enrollment.
- Subgroup and Special Population Studies: Specific studies conducted in pediatric populations (e.g., patients aged 8 to 17 years with NASH), elderly populations, and patients with hepatic or renal impairment have been particularly crucial to meet the regulatory requirements regarding dosing, safety, and efficacy in these groups.
- Drug–Drug Interaction Studies: Following guidelines, studies such as the drug–drug interaction trial with indomethacin have been critical for understanding potential interactions that may affect the pharmacokinetics of Elafibranor, thus informing dosing recommendations.

Over the course of its clinical development, Elafibranor has been subjected to a series of trials that span different phases, focused on several therapeutic indications. These trials have been designed not only to explore efficacy endpoints but also to characterize its pharmacokinetic behavior and safety profile across various populations.

Several completed studies have provided in-depth insights into the effects of Elafibranor:

- Primary Sclerosing Cholangitis (PSC) Trial:
A notable phase II trial assessed the safety and effectiveness of Elafibranor in adult participants with PSC. This trial was structured as a multicenter, double-blind, randomized, placebo-controlled study with an open-label long-term extension, enabling a deep dive into safety and potential efficacy outcomes. The enrollment and early data from this study have contributed to understanding Elafibranor’s role in cholestatic liver disease.

- Primary Biliary Cholangitis (PBC) Trials:
Multiple trials have been conducted in patients with PBC:
- A long-term phase III study evaluated Elafibranor in adult participants with PBC, focusing on both biochemical markers and clinical outcomes.
- Another study investigated Elafibranor as an add-on therapy for PBC in patients with an inadequate response or intolerance to UDCA.
- Subsequent studies, like the phase IIIb trial, further refined the target population by focusing on normalization of alkaline phosphatase (ALP) levels as a surrogate endpoint.
- A phase III open-label study in Japanese participants provided additional regional insights, addressing ethnic differences in drug response.

- Nonalcoholic Steatohepatitis (NASH) Trials:
In the context of NASH, a phase III study compared Elafibranor to placebo in patients with NASH and fibrosis. This study aimed to demonstrate histological improvements and biochemical responses, given the unmet need for NASH treatments.
Additionally, a crossover phase II study evaluated the effect of a short-term 6-week treatment regimen of Elafibranor on hepatic lipid composition in patients with nonalcoholic fatty liver disease (NAFL), offering mechanistic insights into its lipid-lowering effects.

- Pharmacokinetic and Safety Studies in Special Populations:
Several phase I studies have been completed that focus on understanding the pharmacokinetics of Elafibranor in specific populations:
- A trial assessing the effect of food on circulating Elafibranor levels in healthy participants.
- Studies examining PK parameters in hepatic impaired patients and renal impaired patients have informed dosing adjustments necessary for these vulnerable groups.
- An assessment of the pharmacokinetics in elderly volunteers compared to younger adults has helped characterize age-related differences in drug exposure.
- A pediatric study focusing on children and adolescents with NASH expanded the safety database to include younger patients, underpinning future pediatric investigations.
- A repeat-dose study comparing Japanese and non-Asian healthy participants contributed to understanding potential ethnic differences in drug metabolism.

- Drug–Drug Interaction Study:
An important phase I, open-label study evaluated the potential interaction between Elafibranor and indomethacin. By determining how co-administration influences pharmacokinetic parameters, the study provided valuable information for patients likely to be on concomitant medications.

In addition to the completed studies, there are several ongoing clinical trials that continue to refine the therapeutic role of Elafibranor:

- Phase III RESOLVE-IT Trial in NASH:
One of the critical ongoing trials is the large-scale phase III RESOLVE-IT trial. This study is designed to evaluate the long-term clinical outcomes of Elafibranor in patients with NASH and fibrosis. The trial focuses on histological endpoints such as resolution of NASH without worsening fibrosis and also monitors clinical outcomes related to mortality and liver-related complications. Enrollment has reached the required numbers, and long-term data are eagerly awaited to confirm efficacy and safety in a broader population.

- Open-Label Extension Studies:
Several trials have incorporated open-label extensions to evaluate the long-term effects of Elafibranor. For instance, the long-term extension of the PSC trial and the PBC studies aim to capture the durability of the therapeutic response, safety over extended treatment durations, and potential benefits on disease progression.

- Special Population Expansion:
Ongoing investigations continue to assess Elafibranor in specific patient demographics such as pediatric populations and in diverse ethnic groups as outlined in the repeat-dose study. These studies are essential to refine dosing and ensure safety across global populations.

The outcomes of these trials, both completed and ongoing, have significantly contributed to the body of evidence surrounding Elafibranor:

- Efficacy in Cholestatic Liver Diseases:
In the phase III studies concentrating on PBC, a statistically significant improvement in biochemical markers such as alkaline phosphatase normalization has been observed in patients treated with Elafibranor compared to placebo. The trials highlight a substantial reduction in cholestatic injury markers which correlate with improved liver function. In addition, data from regional studies, such as the Japanese PBC trial, affirm that these findings extend across diverse populations.

- Efficacy in NASH:
The RESOLVE-IT phase III trial in NASH patients has provided robust data regarding the histological improvements seen with Elafibranor treatment. Although the detailed histological endpoints, such as NASH resolution rates and fibrosis improvement, are still being fully analyzed in long-term follow-up studies, interim results have indicated a trend towards improvement in hepatic steatosis, inflammation, and fibrosis. Complementary data from the shorter phase II crossover study support the concept that Elafibranor favorably modifies hepatic lipid composition—a critical component of the pathophysiology of NASH.

- Pharmacokinetic and Safety Profiles:
The panoply of phase I studies has consistently demonstrated that Elafibranor has an acceptable safety profile with predictable pharmacokinetics. Studies in healthy volunteers have shown that food intake, age, and repeated dosing produce manageable and reversible effects on drug levels. In populations with hepatic or renal impairment, dose adjustments have been proposed based on observed changes in drug clearance. Additionally, the drug–drug interaction study with indomethacin has contributed key data to its clinical pharmacology package, ensuring that clinicians can safely prescribe Elafibranor alongside common concomitant medications without significant risk of adverse interactions.

- Special Populations:
The pediatric study and the ethnic population comparison bolster the notion that Elafibranor can be administered safely to a wide range of patients. These studies pave the way for future expansion into populations that were historically difficult to study in hepatology clinical trials, ensuring that knowledge regarding dosing and safety is applicable in real-world clinical settings.

- Biomarker and Endpoint Analyses:
Using biochemical markers such as ALP, total bilirubin, and various inflammatory/ metabolic parameters as surrogate endpoints has provided a multi-dimensional picture of the drug's activity. The correlation between these biomarkers and clinical outcomes in both PBC and NASH trials indicates that Elafibranor not only improves laboratory test results but may also offer direct clinical benefits in terms of disease progression and patient quality of life. The comprehensive analytical strategies employed in these trials have been designed to address potential challenges in long-term data collection and interpretation, ensuring that the results are both robust and clinically meaningful.

The extensive clinical trial program for Elafibranor has had far-reaching implications not only for its future therapeutic development but also for the field of hepatology as a whole. Insights gained from both the completed and ongoing trials provide a solid foundation for optimizing treatment guidelines, further refining patient selection criteria, and exploring combination regimens with other therapeutic agents.

The results observed in these clinical trials offer significant potential to influence treatment guidelines for liver diseases:
- Cholestatic Liver Diseases (PBC/PSC):
The consistent biochemical improvements in ALP normalization and bilirubin levels in PBC patients suggest that Elafibranor could become a key second-line therapy for patients who are refractory or intolerant to UDCA. The evidence from multiple independent trials provides a strong case for its inclusion in practice guidelines once regulatory approvals have been obtained.
- Nonalcoholic Steatohepatitis (NASH):
Given the unmet therapeutic needs for NASH, the promising effects observed in phase III trials and supportive lipid composition data in NAFL studies reinforce the potential role of Elafibranor as an effective treatment option. As further data from the RESOLVE-IT trial become available, clinicians may soon have a new evidence-based therapy to offer patients with a condition for which there is currently no approved pharmacological treatment.
- Special Populations:
The tailored dosing strategies developed from studies focusing on elderly patients, pediatric populations, and those with hepatic or renal impairments provide a framework that may be adopted into future treatment guidelines, ensuring that recommendations are safe and effective across a broad spectrum of patient demographics.

Given the progress made thus far, several key areas for future research emerge:
- Long-Term Outcomes:
Continued follow-up in open-label extensions and long-term phase III trials such as RESOLVE-IT will be necessary to fully document the impact of Elafibranor on clinically meaningful endpoints such as overall survival, prevention of cirrhosis, and reduction in liver-related complications.
- Biomarker-Driven Patient Stratification:
Future studies may focus on refining the patient selection criteria by integrating novel biomarkers that predict response to therapy. The correlation between biochemical endpoints and histological improvement noted in current trials highlights the opportunity to use such biomarkers for design of more targeted therapies.
- Combination Therapy Strategies:
As is increasingly recognized in hepatology, combination therapy—targeting multiple pathways concurrently—may offer better outcomes than monotherapies. Future clinical trials could explore synergistic effects of Elafibranor in combination with other agents such as FXR agonists, GLP-1 receptor agonists, and other emerging therapies.
- Expansion to Other Liver Diseases:
The mechanism of action of Elafibranor suggests potential utility in a broader range of liver disorders. Ongoing and future studies may also investigate its role in acute on chronic liver failure (ACLF) and other metabolic liver diseases, potentially widening its clinical applicability.
- Integration with Innovative Clinical Trial Designs:
The evolution of clinical trial methodologies—especially the use of master protocols, adaptive designs, and real-world evidence—would serve to streamline further development programs. Implementing such approaches in future studies of Elafibranor can help optimize resource utilization and accelerate the pace of clinical decision-making.

In summary, a comprehensive clinical development program for Elafibranor has been executed, which spans early phase I investigations through to large-scale phase III trials, with a multitude of completed and ongoing studies. The trials have been designed in a hierarchical manner that explores the spectrum of safety, pharmacokinetics, and therapeutic efficacy in indications such as PBC, PSC, and NASH. Key completed studies include phase II and III trials in cholestatic liver diseases and NASH, as well as dedicated phase I studies in healthy volunteers, pediatric populations, and those with organ impairments. These studies have demonstrated significant biochemical and histological improvements in patient populations with unmet needs, outlining a clear potential for future incorporation of Elafibranor into clinical treatment guidelines.

From a general perspective, the Elafibranor clinical trials reflect the current trend in the pharmaceutical industry towards multifaceted approaches in addressing complex diseases, particularly in liver pathology. Specifically, the detailed pharmacokinetic and outcome data reinforce the drug’s safety profile while underlining its potential efficacy across various conditions. Moreover, the research not only validates current treatment paradigms but also paves the way for future research directions that include combination therapies and biomarker-driven patient stratification strategies.

From a specific standpoint, the data from each phase—ranging from precise drug–drug interaction studies to large-scale efficacy assessments—provide a robust framework for understanding how Elafibranor modulates key biochemical pathways implicated in liver disease progression. The use of rigorous trial designs, adherence to regulatory requirements, and comprehensive analyses of subgroup populations ensure that the conclusions drawn are both reliable and applicable to real-world clinical settings.

Finally, from a general perspective, the insights acquired from the clinical trials of Elafibranor are not only limited to its current indications but also have broader implications for future drug development in hepatology. Continued research, particularly in long-term outcome studies and adaptive trial designs, promises to further elucidate the full therapeutic potential of Elafibranor and set the stage for improved patient management strategies in liver diseases.

In conclusion, the clinical trials for Elafibranor represent a multifaceted and hierarchical approach to drug development. They have significantly advanced our understanding of the drug’s pharmacological characteristics, therapeutic potential, and safety profile, thereby establishing a strong foundation for its eventual clinical use. With ongoing studies and future research directions poised to address remaining questions, Elafibranor stands as one of the most promising candidates in the management of metabolic and cholestatic liver diseases.