Ervogastat (PF-06865571): A Novel DGAT2 Inhibitor for Metabolic Dysfunction-Associated Steatohepatitis

1. Introduction to Ervogastat (PF-06865571)

Overview and Significance in NASH/MASH Treatment Landscape

Ervogastat, also known by its development code PF-06865571, is an investigational small molecule therapeutic agent currently under development by Pfizer Inc..[1] This compound has garnered attention as a potentially significant advancement in the challenging field of Metabolic Dysfunction-Associated Steatohepatitis (MASH), a condition previously referred to as Non-alcoholic Steatohepatitis (NASH). The focus of ervogastat's development is particularly on patients who present with liver fibrosis, a critical factor in disease progression.[2]

The landscape of MASH treatment is characterized by a profound unmet medical need. It is a progressive liver disease that, until very recently, had no therapies approved by major regulatory bodies like the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA).[4] The potential consequences of untreated MASH are severe, including the development of cirrhosis, liver failure, and hepatocellular carcinoma, underscoring the urgency for effective pharmacological interventions.[4]

Ervogastat is distinguished as a first-in-class inhibitor of Diacylglycerol O-Acyltransferase 2 (DGAT2).[2] This classification is noteworthy because it signifies a novel therapeutic mechanism. By targeting DGAT2, ervogastat intervenes in key lipid metabolic pathways that are understood to be central to the pathogenesis of MASH. The "first-in-class" status implies that, if proven successful, ervogastat could not only offer a much-needed treatment option but also serve to validate DGAT2 inhibition as a viable therapeutic strategy for MASH. Such validation could stimulate further research and development of other agents within this drug class, potentially broadening the future armamentarium against this complex disease.

The consistent emphasis throughout ervogastat's development program on "MASH with liver fibrosis" points to a strategically targeted approach. Liver fibrosis is recognized as the most significant predictor of adverse long-term outcomes in MASH, including liver-related mortality and the necessity for liver transplantation.[6] Regulatory agencies, in their evaluation of new MASH therapies, often prioritize endpoints that demonstrate an improvement in fibrosis or resolution of steatohepatitis without the worsening of fibrosis.[8] By concentrating on this patient subpopulation, who are at a higher risk of progressing to severe liver disease, the development program aims to address the most critical aspects of MASH. This focus is aligned with demonstrating meaningful clinical benefit as per regulatory expectations, potentially streamlining the pathway to approval if efficacy in mitigating fibrosis is clearly established.

Furthermore, the evolution of medical terminology from NAFLD/NASH to Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) and MASH, which has occurred during ervogastat's development period, reflects a refined understanding of the disease.[6] The older nomenclature primarily served to exclude alcohol as a causative factor. In contrast, the newer terms emphasize the integral role of systemic metabolic dysfunction as a core diagnostic criterion.[7] Ervogastat's mechanism of action, which involves the inhibition of DGAT2 and thereby the synthesis of triglycerides—a fundamental metabolic process—directly corresponds with addressing this "metabolic dysfunction" component of MASH. This alignment enhances its relevance and strengthens its positioning within the evolving diagnostic and therapeutic paradigms for steatotic liver diseases.

Developer: Pfizer Inc.

Pfizer Inc. is consistently identified across a multitude of sources, including its own pipeline updates, clinical trial registries, and scientific publications, as the originator and developer of ervogastat (PF-06865571).[1]

2. Pharmacological Profile of Ervogastat

2.1. Chemical Identity

Ervogastat is a small molecule drug candidate. Its key chemical identifiers are as follows:

• Generic Name: Ervogastat.[1]
• Development Code: PF-06865571.[1]
• CAS Number: 2186700-33-2.[19]
• Molecular Formula: C21​H21​N5​O4​.[19]
• Molecular Weight: Approximately 407.42 g/mol.[19]
• Chemical Structure:
• IUPAC Name: 2-[5-(3-ethoxypyridin-2-yl)oxypyridin-3-yl]-N-pyrimidine-5-carboxamide.[21]
• SMILES: CCOC1=C(N=CC=C1)OC2=CN=CC(=C2)C3=NC=C(C=N3)C(=O)N[C@H]4CCOC4.[21]
• InChIKey: UKBQFBRPXKGJPY-INIZCTEOSA-N.[21]
• 2D Structure:      O=C(N[C@@H]1CCOC1)C2=CN=C(C=N2)C3=CC(OC4=NC=CC=C4OCC)=CN=C3 (Structure based on SMILES string, visual representation typically sourced from chemical databases like PubChem)
• Drug Class: Classified as a small molecule. Further categorized under Amides; Ethers; Furans; Pyridines; Pyrimidines based on its chemical moieties.[1]

2.2. Mechanism of Action: DGAT2 Inhibition and its Metabolic Consequences

Ervogastat functions as a potent and selective inhibitor of the enzyme Diacylglycerol O-Acyltransferase 2 (DGAT2).[1] DGAT2 is a pivotal enzyme in lipid metabolism, primarily responsible for catalyzing the final and rate-limiting step in the synthesis of triglycerides (TGs) within various tissues, with a particularly significant role in the liver. This enzyme also contributes to the broader regulation of energy metabolism.[3] Notably, DGAT2 shows a preference for utilizing de novo-synthesized fatty acids as substrates for triglyceride assembly.[29]

The therapeutic rationale for inhibiting DGAT2 in the context of MASH stems from the enzyme's role in triglyceride production. By blocking DGAT2 activity, ervogastat aims to curtail the excessive synthesis and subsequent accumulation of triglycerides in hepatocytes, a condition known as hepatic steatosis, which is a defining characteristic of NAFLD and its progressive form, MASH.[3]

It is hypothesized that this reduction in hepatic fat content will, in turn, alleviate lipotoxicity. Lipotoxicity refers to the cellular damage and dysfunction caused by the accumulation of excess lipids and their metabolites. By mitigating lipotoxicity, DGAT2 inhibition is anticipated to lead to downstream improvements in related pathological processes, including hepatic inflammation, hepatocellular injury, and potentially the progression of liver fibrosis.[4]

The development of ervogastat was informed by experiences with an earlier, prototype liver-targeted DGAT2 inhibitor, PF-06427878. A key aspect of ervogastat's design was the circumvention of potential developmental risks associated with this prototype. Specifically, medicinal chemistry efforts focused on replacing a metabolically labile motif within PF-06427878. This modification was crucial to prevent the cytochrome P450-mediated O-dearylation that could lead to the formation of reactive quinone metabolites, which pose a safety concern.[2] This strategic chemical modification underscores a sophisticated approach to drug design, aiming to enhance the safety profile for a therapy intended for chronic conditions like MASH. For such long-term treatments, a clean safety record is paramount. The proactive measures to de-risk ervogastat from potential idiosyncratic drug-induced liver injury (DILI) or other toxicities, by preventing the formation of reactive metabolites, reflect a hallmark of modern medicinal chemistry and are intended to increase the likelihood of clinical success.

An important distinction in the mechanism and potential tolerability of DGAT2 inhibitors like ervogastat relates to the differential tissue expression of DGAT isoforms. DGAT1, another enzyme involved in triglyceride synthesis, is highly expressed in the intestine. Inhibition of DGAT1 has been associated with gastrointestinal side effects. In contrast, DGAT2 exhibits minimal expression in the intestine and is enriched in hepatocytes.[29] This tissue-specific expression profile suggests that selective DGAT2 inhibition by ervogastat is less likely to cause the dose-limiting gastrointestinal adverse events observed with DGAT1 inhibitors. This improved tolerability is a significant advantage for a chronic therapy and was noted as a positive attribute of ervogastat in reviews, which mentioned its efficacy on liver steatosis "without serious gastrointestinal adverse events".[12] This makes DGAT2 a more attractive therapeutic target for chronic conditions.

2.3. Pharmacokinetics (Absorption, Distribution, Metabolism, Excretion, Drug-Drug Interactions)

The pharmacokinetic profile of ervogastat has been investigated in several studies to understand its behavior in the body.

• Absorption: Ervogastat is designed for oral administration.[8] Clinical trial protocols have indicated that food can significantly increase the exposure to ervogastat. Consequently, dosing in these trials has often been specified to occur with meals to ensure consistent absorption.[27]
• Metabolism: The primary route of metabolism for ervogastat is through the Cytochrome P450 3A (CYP3A) enzyme system.[27] In vitro studies have also suggested that ervogastat itself may act as an inducer of CYP3A.[27] The chemical design of ervogastat specifically aimed to achieve improved metabolic stability compared to earlier drug candidates in its class.[2]
• Elimination Half-life: Following single oral doses, the terminal elimination half-life of ervogastat has been reported to be in the range of approximately 1.45 to 5.22 hours.[27] This relatively short half-life is a key characteristic that often necessitates multiple daily doses to maintain therapeutic drug concentrations. This is reflected in the twice-daily (BID) dosing regimens employed in several of its clinical trials.[8]
• Drug-Drug Interactions (DDI):
• The potential for interactions with other drugs is an important consideration, particularly given its CYP3A-mediated metabolism. A dedicated DDI study (NCT03534648) evaluated the co-administration of ervogastat with clesacostat (PF-05221304), an Acetyl-CoA Carboxylase (ACC) inhibitor. Clesacostat itself is a potential time-dependent inactivator of CYP3A in vitro. Despite these in vitro observations, the clinical study found that co-administration of ervogastat (300 mg BID) with clesacostat (15 mg BID) was safe and did not result in any clinically meaningful pharmacokinetic interactions. A modest decrease in mean systemic clesacostat exposure (by 12-19%) was observed when given with ervogastat.[27] These findings were supportive of progressing the combination therapy into Phase 2 trials.[27]
• In vitro studies have also identified ervogastat as a substrate for the efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Furthermore, ervogastat may itself inhibit P-gp and BCRP in vitro.[27]
• Specific Populations:
• To understand the pharmacokinetic behavior of ervogastat in patients with liver disease, a Phase 1 study (NCT04091061, Pfizer protocol C2541009) was designed. This study aimed to compare the pharmacokinetics of a single dose of PF-06865571 in adult participants with varying degrees of hepatic impairment against those with normal hepatic function.[30] The results from such a study are critical for determining if dose adjustments are necessary for patients with pre-existing liver conditions, a common characteristic of the target MASH population.

The pharmacokinetic profile of ervogastat, characterized by its short half-life and interactions with the CYP3A system, suggests that patient management will require careful attention to dosing schedules and a thorough review of potential co-medications. The BID dosing regimen, while necessary to maintain exposure, could influence patient adherence. Moreover, since MASH patients frequently present with comorbidities such as type 2 diabetes, dyslipidemia, and hypertension, they are often on multiple concurrent medications.[23] This scenario elevates the risk of DDIs. Thus, comprehensive DDI evaluations, like the study with clesacostat, are vital. Clinicians will need to exercise vigilance regarding co-prescribed drugs, and the observed food effect on absorption adds another dimension to consider when providing dosing instructions.

Table 1: Chemical and Pharmacological Properties of Ervogastat (PF-06865571)

Parameter	Details	Reference(s)
Generic Name	Ervogastat	1
Development Code	PF-06865571	1
CAS Number	2186700-33-2	19
Molecular Formula	C21​H21​N5​O4​	19
Molecular Weight	~407.42 g/mol	19
IUPAC Name	2-[5-(3-ethoxypyridin-2-yl)oxypyridin-3-yl]-N-pyrimidine-5-carboxamide	21
SMILES	CCOC1=C(N=CC=C1)OC2=CN=CC(=C2)C3=NC=C(C=N3)C(=O)N[C@H]4CCOC4	21
Target Enzyme	Diacylglycerol O-Acyltransferase 2 (DGAT2)	1
Mechanism of Action	Potent and selective inhibition of DGAT2, reducing triglyceride synthesis	3
Drug Class	Small molecule; Amides; Ethers; Furans; Pyridines; Pyrimidines	1

3. Preclinical Research and Development

3.1. Discovery and Design Rationale

The development of ervogastat (PF-06865571) was a targeted effort to overcome limitations identified in an earlier, prototype liver-targeted DGAT2 inhibitor known as PF-06427878.[2] This iterative approach is common in drug discovery, where initial candidates provide valuable insights that guide the design of improved, next-generation molecules.

Two key design strategies were pivotal in the evolution from PF-06427878 to ervogastat [2]:

1. Modification of a Metabolically Labile Motif: The prototype compound, PF-06427878, contained a chemical group susceptible to metabolic breakdown. Specifically, there was a concern that cytochrome P450-mediated O-dearylation could lead to the formation of a reactive quinone metabolite precursor. Such reactive metabolites are often implicated in drug-induced toxicity. To mitigate this safety risk, the metabolically labile motif was replaced with a more stable 3,5-disubstituted pyridine system in ervogastat.
2. Optimization of the Amide Group: Further refinements involved modifying the amide portion of the molecule to a 3-THF (tetrahydrofuran) group. This change was not arbitrary but was guided by detailed metabolite identification studies of earlier compounds, coupled with property-based drug design principles. The aim of this modification was to optimize the pharmacokinetic properties of the drug, such as its absorption, distribution, metabolism, and excretion (ADME) profile.

The overarching goal of these chemical modifications was to create a systemically acting DGAT2 inhibitor that possessed an improved metabolic stability and a more favorable safety profile compared to its predecessor.[2] This "fast-follower" or "second-generation" strategy within Pfizer's DGAT2 inhibitor program, learning from and actively mitigating the risks identified with PF-06427878, represents a sophisticated and rational approach to drug development. Such an iterative process, focused on enhancing safety and pharmacokinetic characteristics, is crucial for developing therapies intended for chronic conditions like MASH, where long-term administration is anticipated.

3.2. Key In Vitro Efficacy and Selectivity

Ervogastat is consistently described in scientific literature as a "potent and selective" inhibitor of the DGAT2 enzyme.[2] The primary research article detailing its discovery and initial characterization, published by Futatsugi et al. in the Journal of Medicinal Chemistry (2022), serves as a key reference for its early pharmacological properties.[3]

While the abstract of this publication confirms the compound's potency and selectivity, the specific quantitative measures, such as the half-maximal inhibitory concentration (IC50​) value against human DGAT2 and the precise selectivity ratio when compared to DGAT1 (the other major DGAT isoform), are typically found within the main body of the full research paper or, more commonly, in its detailed supporting information files.[37] The supporting information for the Futatsugi et al. (2022) paper is explicitly stated to include in vitro selectivity data for related compounds and supplementary in vitro pharmacology data for ervogastat itself (referred to as compound 6 in that publication).[37] Access to these detailed supplementary materials is necessary to ascertain the exact figures for potency and selectivity.

3.3. In Vivo Efficacy in Animal Models of NAFLD/NASH

Preclinical studies conducted in various laboratory animal models have provided evidence for the in vivo activity of ervogastat, particularly when investigated in combination with the ACC inhibitor, clesacostat. These studies indicated that the co-administration of clesacostat and ervogastat led to improvements in NAFLD/NASH-related endpoints. A significant finding was the mitigation of clesacostat-induced elevations in serum triglycerides, a known side effect of ACC inhibition.[27] Furthermore, these non-clinical investigations suggested that the combination therapy yielded greater efficacy in reducing liver fat content, as well as ameliorating inflammation and fibrosis, compared to the effects observed with either monotherapy.[27] This preclinical synergy and the ability to counteract a specific side effect of ACC inhibition provided a strong scientific basis for advancing the combination therapy into clinical trials.

While specific quantitative results from in vivo animal studies focusing solely on ervogastat monotherapy (such as the percentage reduction in liver fat, the doses used, and details of the animal models employed) are not extensively detailed in the summarized snippets, such information would typically be present in the full Futatsugi et al. (2022) publication or its comprehensive supporting information.[37] General mechanistic support comes from studies like Liu et al. [29], which, although not directly on ervogastat, demonstrated that DGAT2 inhibition in mice suppressed SREBP-1 cleavage, reduced fatty acid synthesis, and lowered triglyceride accumulation, aligning with the expected downstream effects of ervogastat.

3.4. Preclinical Safety and Toxicology Profile

The preclinical safety and toxicology of ervogastat have been evaluated, particularly concerning developmental and reproductive toxicity. Studies conducted in rats indicated that administration of ervogastat during the period of organogenesis led to reduced fetal weight and an increased incidence of bent bones in fetuses. However, these skeletal findings were observed to resolve by postnatal day 28, leading to the conclusion that they were transient variations attributable to a delay in development rather than permanent teratogenic effects.[20]

When dosing in rats was extended throughout gestation and lactation, more pronounced effects were noted, including impaired skin development in offspring, reduced viability of the pups, and growth retardation.[20] These developmental effects were considered consistent with the intended pharmacological action of ervogastat—namely, the alteration of triglyceride metabolism, which is crucial for normal growth and development. The observation that the adverse effects on skin barrier development occurred within a late gestational window of sensitivity helped to somewhat reduce concerns regarding potential adverse effects on human development, though caution remains paramount.[20] Importantly, ervogastat did not demonstrate any adverse effects on female rat fertility or on embryo-fetal development in rabbits.[20]

A significant aspect of ervogastat's safety profile relates to its design. As previously mentioned, it was specifically engineered to avoid the formation of reactive quinone metabolites, a potential issue with the earlier candidate PF-06427878. This proactive design choice aimed to minimize the risk of certain types of toxicity.[2]

The developmental toxicity findings in rats, even though rationalized by the drug's primary pharmacology, underscore the critical role of DGAT2 and triglyceride metabolism in fetal and neonatal development. Triglycerides are fundamental as energy sources and as building blocks for tissues in developing organisms. Pharmacological interference with such a vital process during sensitive developmental periods can logically result in impacts on growth and tissue maturation, such as the observed skin barrier issues. While the rat findings were contextualized, they highlight the necessity for stringent exclusion criteria regarding pregnancy in clinical trials and mandate careful risk-benefit assessment and counseling if the drug were to be considered for use in women of childbearing potential.

4. Clinical Development Program in NAFLD/NASH/MASH

4.1. Overview of Clinical Trials Strategy

Pfizer has orchestrated a comprehensive clinical development program for ervogastat, investigating its potential both as a standalone therapy (monotherapy) and, significantly, in combination with another investigational agent, clesacostat (PF-05221304), which is an Acetyl-CoA Carboxylase (ACC) inhibitor.[4] This dual therapeutic approach reflects an understanding of the multifaceted nature of MASH, suggesting that targeting multiple pathogenic pathways simultaneously might yield superior efficacy.

The program has progressed through various stages, commencing with Phase 1 studies. These initial trials typically involve healthy volunteers to assess safety, tolerability, and pharmacokinetics, as well as studies in specific patient populations, such as those with hepatic impairment, to understand drug disposition under varied physiological conditions. Following these, Phase 2a studies were conducted, primarily focusing on demonstrating proof-of-concept by measuring reductions in liver fat content in individuals with NAFLD. The culmination of the Phase 2 efforts is a larger, more definitive Phase 2b study, known as the MIRNA trial. This study enrolled patients with biopsy-confirmed NASH and liver fibrosis and was designed to evaluate ervogastat's impact on key histological endpoints, which are critical for regulatory assessment.[5]

A notable strategic component of ervogastat's development is the strong emphasis on its combination with clesacostat. This combination therapy has been granted Fast Track designation by the U.S. FDA for the treatment of NASH with liver fibrosis, signaling regulatory acknowledgement of its potential to address a serious unmet medical need.[4] The rationale for this combination is rooted in the distinct but complementary mechanisms of DGAT2 and ACC inhibition, which target different steps in lipid synthesis. Preclinical and early clinical data have supported this approach, particularly with ervogastat showing the ability to mitigate hypertriglyceridemia, a side effect associated with ACC inhibitors.

The progression from studies in NAFLD patients focusing on surrogate markers like MRI-PDFF (a non-invasive measure of liver fat) to a larger Phase 2b trial in biopsy-confirmed NASH with F2-F3 fibrosis using histological endpoints represents a standard and rigorous drug development pathway for MASH therapies. Early-phase trials utilize non-invasive markers to establish initial efficacy on steatosis. However, for regulatory approval, especially when claiming effects on fibrosis, improvements in liver histology (such as NASH resolution or fibrosis regression) assessed via liver biopsy are typically required by agencies like the FDA and EMA.[8] The MIRNA trial's design, with its biopsy-confirmed patient cohort and histological primary endpoints, directly addresses these regulatory expectations. It aims to demonstrate a clinically meaningful benefit that extends beyond simple liver fat reduction to include improvements in the defining pathological features of NASH and fibrosis.

Table 2: Overview of Key Clinical Trials for Ervogastat (PF-06865571)

Trial ID (NCT/EudraCT)	Phase	Condition(s)	Intervention(s)	Key Objective(s)/Primary Endpoint(s)	Status	Reference(s)
NCT03593707	1	Healthy Volunteers	Ervogastat	Safety, Tolerability, PK	Completed	19
NCT03513588	1	Non-alcoholic Steatohepatitis (NASH), Non-alcoholic Fatty Liver Disease (NAFLD)	Ervogastat	Safety, Tolerability, PK, Early PD (liver fat)	Completed	19
NCT04091061 (C2541009)	1	Hepatic Impairment (varying degrees vs. healthy)	Ervogastat (single dose)	Pharmacokinetics (AUC, Cmax) in hepatic impairment	Not explicitly stated, likely Completed based on SAP date	30
NCT03534648	1	Healthy Volunteers	Ervogastat, Clesacostat (PF-05221304)	PK Drug-Drug Interaction, Safety	Completed	27
NCT03776175 (C3711001)	2a	Non-Alcoholic Fatty Liver Disease (NAFLD)	Ervogastat (300mg BID), Clesacostat (15mg BID), Combination, Placebo	Percent change from baseline in liver fat (MRI-PDFF) at 6 weeks	Completed	23
NCT04321031 (MIRNA / C2541013 / EudraCT 2019-004775-39)	2b	Biopsy-confirmed NASH with Fibrosis (F2-F3)	Ervogastat (25-300mg QD/BID), Clesacostat (5-10mg BID), Combination, Placebo	Proportion achieving NASH resolution w/o worsening fibrosis OR ≥1 stage fibrosis improvement w/o worsening NASH, OR both, at Week 48	Completed	4
NCT03711005 (C3711005)	2a	Sponsor-defined Presumed NASH	Ervogastat (25, 100, 300mg) + Clesacostat (10, 20mg), Placebo	Change in liver fat	Completed	24

PK: Pharmacokinetics; PD: Pharmacodynamics; AUC: Area Under the Curve; Cmax: Maximum Concentration; MRI-PDFF: Magnetic Resonance Imaging Proton Density Fat Fraction; QD: Once Daily; BID: Twice Daily.

4.2. Phase 1 Clinical Studies

Several Phase 1 clinical studies have been conducted to evaluate the initial safety, tolerability, and pharmacokinetic (PK) profile of ervogastat (PF-06865571), both as a single agent and in combination, in healthy volunteers and in patients with liver conditions.

• NCT03593707: This was a Phase 1 study conducted in healthy volunteers. It has been reported as completed.[19] While specific objectives and outcomes are not detailed in the provided materials, such first-in-human studies typically focus on assessing the safety and tolerability of ascending doses of the investigational drug and characterizing its pharmacokinetic profile.
• NCT03513588: Also a Phase 1 study, this trial enrolled patients with Non-alcoholic Steatohepatitis (NASH) or Non-alcoholic Fatty Liver Disease (NAFLD) and is reported as completed.[19] The objectives likely included evaluating the safety, tolerability, and PK of ervogastat in the target patient population. Importantly, early pharmacodynamic data from studies such as this indicated that oral administration of ervogastat for 14 days led to dose-dependent reductions in both liver fat and serum triglycerides in individuals with NAFLD.[25]
• NCT04091061 (Pfizer Protocol C2541009): This Phase 1 study was a non-randomized, open-label, single-dose, parallel-cohort trial designed specifically to compare the pharmacokinetics of PF-06865571 in adult participants with varying degrees of hepatic impairment (mild, moderate, severe) relative to participants with normal hepatic function.[30] The primary endpoints focused on key PK parameters such as Area Under the Curve (AUC) and maximum plasma concentration (Cmax). Safety assessments, including adverse events (AEs), clinical laboratory tests, vital signs, and 12-lead electrocardiograms (ECGs), were also integral to the study.[30] The findings from this trial are crucial for determining if dose adjustments are needed when administering ervogastat to patients with pre-existing liver dysfunction.
• NCT03534648: This Phase 1 study was an open-label, non-randomized, fixed-sequence, multiple-dose trial in healthy volunteers. Its primary objective was to investigate the potential for a pharmacokinetic drug-drug interaction (DDI) between clesacostat (PF-05221304, an ACC inhibitor) and ervogastat (PF-06865571).[27]
• Key Finding: The study established that co-administration of ervogastat 300 mg twice daily (BID) with clesacostat 15 mg BID was safe and did not result in any clinically meaningful PK DDI. While mean systemic clesacostat exposures (AUC and Cmax) showed a modest decrease of 12% and 19%, respectively, when co-administered with ervogastat, this was not considered clinically significant.[27] These results were important in supporting the progression of the ervogastat and clesacostat combination to Phase 2 clinical trials in patients with NAFLD/NASH.[27]

4.3. Phase 2a Clinical Study in NAFLD (NCT03776175 / Pfizer Protocol C3711001): Ervogastat Monotherapy and Combination with Clesacostat

The Phase 2a clinical trial, identified by NCT03776175 (Pfizer Protocol C3711001), was a pivotal study in evaluating the early efficacy and safety of ervogastat in patients with Non-Alcoholic Fatty Liver Disease (NAFLD). This study was designed as a randomized, double-blind (though sponsor-open, meaning the sponsor was aware of treatment assignments for operational purposes while investigators and patients remained blinded), placebo-controlled, parallel-group investigation. The primary focus was on assessing the pharmacodynamics, safety, and tolerability of ervogastat, both as a monotherapy and when co-administered with the ACC inhibitor clesacostat (PF-05221304).[23] The treatment duration for this study was 6 weeks.[23]

• Patient Population: The trial enrolled adult participants diagnosed with NAFLD. A subset of these patients also had co-existing Type 2 Diabetes Mellitus (T2DM).[23]
• Interventions and Dosing Regimens: Participants were randomized to one of several treatment arms [23]:
• Ervogastat (PF-06865571) monotherapy: 300 mg administered twice daily (BID). The number of patients in this arm for some analyses was 24.[28]
• Clesacostat (PF-05221304) monotherapy: 15 mg administered BID. The number of patients in this arm for some analyses was 22.[28]
• Combination Therapy: Ervogastat 300 mg BID co-administered with Clesacostat 15 mg BID. The number of patients in this arm for some analyses was 26.[28]
• Placebo: The number of patients in the placebo arm was 14 according to one source [23], and 12 for some specific analyses.[28]
• Efficacy Outcomes:
• Primary Endpoint: The main measure of efficacy was the percent change from baseline in liver fat content, as assessed by Magnetic Resonance Imaging–Proton Density Fat Fraction (MRI-PDFF) at the end of the 6-week treatment period.[28]
• Liver Fat Reduction (MRI-PDFF at 6 weeks): Significant reductions in liver fat were observed in the active treatment arms compared to placebo.[23]
• Combination Therapy (Ervogastat + Clesacostat): This arm demonstrated a robust reduction in liver fat, with values around 40-45.8% from baseline. The placebo-adjusted least squares mean (LSM) (90% Confidence Interval, CI) reduction was -44.6% (-54.8, -32.2).
• Ervogastat Monotherapy: This arm showed a liver fat reduction of approximately 30% from baseline. The placebo-adjusted LSM (90% CI) reduction was -35.4% (-47.4, -20.7).
• Clesacostat Monotherapy: This arm resulted in a liver fat reduction of about 40% from baseline. The placebo-adjusted LSM (90% CI) reduction was -44.5% (-55.0, -31.7).
• Placebo: In contrast, the placebo group experienced an increase in liver fat of approximately 8%.
• Serum Triglycerides: A notable finding concerned serum triglyceride levels. Clesacostat monotherapy, consistent with the known class effects of ACC inhibitors, led to a dose-dependent elevation in serum triglycerides. However, the co-administration of ervogastat with clesacostat effectively mitigated this ACC inhibitor-mediated increase in triglycerides.[28] This observation is particularly important as it suggests a way to overcome a significant adverse effect associated with ACC inhibition.
• Other Lipids: The study also assessed changes in other lipid parameters, including total cholesterol, HDL-cholesterol (HDL-C), and LDL-cholesterol (LDL-C). Data for these were presented as LSM (90% CI) relative to placebo.[28]
• Safety and Tolerability: Ervogastat was generally reported as well-tolerated in this study.[23]
• In the combination therapy arm (Ervogastat + Clesacostat), adverse events (AEs) were reported in 10 out of 28 participants (36%). Importantly, there were no discontinuations from the study due to AEs in this combination arm.[28]
• Specific adverse event details for the ervogastat monotherapy arm were not extensively detailed in the summarized source materials.[28]
• Publication: The results of this Phase 2a study (NCT03776175) were published in the journal Nature Medicine, highlighting its significance in the field.[4]

The completion of this Phase 2a study (NCT03776175) and the subsequent Phase 2a study (NCT03711005, which also showed liver fat reductions with various ervogastat and clesacostat combination doses [24]), provided critical proof-of-concept data. These findings demonstrated ervogastat's ability to reduce liver fat, both alone and in combination, and importantly, showed the combination's potential to mitigate clesacostat-induced hypertriglyceridemia. This formed a strong basis for progressing to larger, longer-duration studies focused on histological outcomes in patients with more advanced NASH.

Table 3: Summary of Efficacy and Safety Results from Phase 2a Study NCT03776175 in NAFLD Patients (6 Weeks Treatment)

Outcome Measure	Ervogastat Monotherapy (300mg BID) (N≈24)	Clesacostat Monotherapy (15mg BID) (N≈22)	Ervogastat (300mg BID) + Clesacostat (15mg BID) Combination (N≈26)	Placebo (N≈12-14)	Reference(s)
Efficacy
Approx. Mean % Change in MRI-PDFF from Baseline	~ -30%	~ -40%	~ -40% to -45.8%	~ +8%	23
Placebo-Adjusted LSM % Change in MRI-PDFF (90% CI)	-35.4% (-47.4, -20.7)	-44.5% (-55.0, -31.7)	-44.6% (-54.8, -32.2)	N/A	28
Change in Serum Triglycerides	Reduction (dose-dependent in earlier studies)	Elevation (dose-dependent class effect)	ACCi-induced elevation mitigated	Minimal change	25
Safety
Adverse Events (AEs) Reported	Not specifically detailed for monotherapy	Not specifically detailed for monotherapy	10/28 (36%) participants	Not specifically detailed	28
Discontinuations due to AEs	Not specifically detailed for monotherapy	Not specifically detailed for monotherapy	0/28 (0%)	Not specifically detailed	28

LSM: Least Squares Mean; CI: Confidence Interval; MRI-PDFF: Magnetic Resonance Imaging Proton Density Fat Fraction; ACCi: Acetyl-CoA Carboxylase inhibitor. N values are approximate based on available data for analyses.

4.4. Phase 2b Clinical Study in NASH with Fibrosis (MIRNA Trial - NCT04321031 / EudraCT 2019-004775-39 / Pfizer Protocol C2541013)

The MIRNA (Metabolic Interventions to Resolve Non-alcoholic Steatohepatitis with Fibrosis) trial represents a significant step in the clinical development of ervogastat, moving into a more advanced patient population with biopsy-proven NASH and liver fibrosis.[22]

• Study Design: This was a Phase 2b, randomized, double-blind, double-dummy, placebo-controlled, dose-ranging, dose-finding, parallel-group study. A key feature of the design was a run-in period of at least 6 weeks, followed by a 48-week double-blind, double-dummy dosing period.[8]
• Patient Population: The trial aimed to enroll approximately 450 adult participants who had biopsy-confirmed NASH along with liver fibrosis stages F2 or F3. To identify eligible participants, a triage approach was employed, which included double-confirmation using non-invasive markers (e.g., quantitative ultrasound like FibroScan) prior to the screening/baseline liver biopsy.[8]
• Interventions and Dosing Regimens: The study evaluated several dosing regimens of ervogastat (DGAT2i) both as monotherapy and in combination with clesacostat (ACCi), compared to placebo [8]:
• Ervogastat monotherapy: Doses ranged from 25 mg to 300 mg, administered either twice per day (BID) or once per day (QD). Specific tablet strengths mentioned in the EudraCT registration include 25 mg, 50 mg, and 150 mg for DGAT2i (ervogastat).
• Combination Therapy: Ervogastat at doses of 150 mg to 300 mg BID, co-administered with Clesacostat at doses of 5 mg to 10 mg BID.
• Matching placebo was used to maintain blinding.
• Primary Outcome Measure: The primary efficacy endpoint was a composite histological outcome assessed at Week 48 by central pathologists. It was defined as the proportion of participants achieving either:

1. Resolution of NASH (defined as NAFLD Activity Score for inflammation = 0-1, ballooning = 0, and steatosis = any score) without worsening of liver fibrosis (no increase in fibrosis stage), OR
2. An improvement in liver fibrosis by ≥1 stage (according to the NASH CRN fibrosis staging system) without worsening of NASH (defined as no increase in ballooning, inflammation, or steatosis scores from baseline), OR
3. Both resolution of NASH and ≥1 stage improvement in fibrosis.[5]

• Key Secondary Outcome Measures: Several secondary endpoints were defined to further assess the efficacy and safety of the interventions [8]:
• Percent change from baseline in liver fat content, measured by MRI-PDFF (this was part of an imaging substudy).
• Proportion of participants achieving the individual components of the primary composite endpoint:
• Resolution of NASH without worsening of fibrosis.
• Improvement in fibrosis by ≥1 stage without worsening of NASH.
• Proportion of participants achieving an improvement in fibrosis by ≥2 stages without worsening of NASH.
• Proportion of participants achieving an improvement of ≥2 points in the Total NAFLD Activity Score (NAS).
• Comprehensive assessment of safety and tolerability, including treatment-emergent adverse events (TEAEs), safety-related clinical laboratory tests, vital signs, and 12-lead ECGs. All histological secondary endpoints were also assessed at Week 48.
• Current Status: The MIRNA trial (NCT04321031 / EudraCT 2019-004775-39) has been completed. The global end of trial date is listed as February 21, 2024.[33] Previous reports had anticipated completion in 2024.[4] The results from this crucial study are expected to inform decisions regarding a potential Phase 3 development program for ervogastat, particularly for the combination therapy with clesacostat.[4] As of Pfizer's pipeline updates in early 2025, ervogastat monotherapy and the ervogastat + clesacostat combination remain listed in Phase 2 for MASH, suggesting that the analysis of MIRNA data is likely ongoing or that plans for further development are under consideration based on these outcomes.[15]

The completion of the MIRNA trial is a significant milestone. The forthcoming data on ervogastat's efficacy in achieving NASH resolution and fibrosis improvement will be critically important in determining its future trajectory and potential role as a therapeutic agent for MASH. These results will be evaluated in the context of a competitive and evolving MASH treatment landscape, especially with the recent approval of the first MASH-specific therapy. Positive outcomes from MIRNA would represent a major advancement for Pfizer's MASH program.

Table 4: Summary of Primary and Key Secondary Endpoints for Phase 2b MIRNA Trial (NCT04321031 / EudraCT 2019-004775-39)

Endpoint Type	Specific Endpoint Description	Timepoint of Assessment	Reference(s)
Primary	Proportion of participants achieving histological NASH resolution without worsening of fibrosis OR ≥1 stage improvement in fibrosis without worsening of NASH OR both	Week 48	5
Secondary	Percent change in liver fat (assessed via MRI-PDFF in substudy population)	Week 48 (and other timepoints)	8
Secondary	Proportion of participants achieving resolution of NASH, without worsening of fibrosis	Week 48	8
Secondary	Proportion of participants achieving improvement in fibrosis by ≥1 stage, without worsening of NASH	Week 48	8
Secondary	Proportion of participants achieving improvement in fibrosis by ≥2 stages, without worsening of NASH	Week 48	8
Secondary	Proportion of participants achieving improvement of ≥2 points in Total NAFLD Activity Score (NAS)	Week 48	8
Secondary	Assessment of TEAEs, safety related clinical laboratory tests, vital signs, and 12-lead ECGs	Over time up to Week 48	8

5. Integrated Efficacy Analysis

5.1. Impact on Liver Fat Accumulation (Steatosis)

Ervogastat has consistently demonstrated a capacity to reduce hepatic steatosis, a primary pathological feature of NAFLD and MASH. This effect has been observed both when ervogastat is administered as a monotherapy and when used in combination with the ACC inhibitor, clesacostat.

• Ervogastat Monotherapy: Early clinical investigations provided evidence of ervogastat's direct impact on liver fat. In a Phase 1 study involving patients with NAFLD, oral administration of ervogastat for a period of 14 days resulted in dose-dependent reductions in liver fat content, as measured by MRI-PDFF. These studies also noted concomitant dose-dependent reductions in serum triglycerides.[25] Further supporting these findings, the Phase 2a study (NCT03776175), which involved a 6-week treatment duration, showed that ervogastat monotherapy at a dose of 300 mg BID led to an approximate 30% reduction in liver fat from baseline. When adjusted for placebo effects, this translated to a least squares mean (LSM) reduction of -35.4%.[23]
• Combination Therapy (Ervogastat + Clesacostat): The combination of ervogastat with clesacostat has generally shown a more pronounced or comparable effect on liver fat reduction compared to ervogastat monotherapy in direct comparisons. In the NCT03776175 study, the combination of ervogastat (300 mg BID) and clesacostat (15 mg BID) resulted in a liver fat reduction of approximately 40-45.8% from baseline, with a placebo-adjusted LSM reduction of -44.6%.[23] Another Phase 2a study (NCT03711005, also referred to as C3711005) investigated various doses of ervogastat (ranging from 25 mg BID to 300 mg BID/QD) co-administered with clesacostat (10 mg BID or 20 mg QD) for 6 weeks. This study also reported significant liver fat reductions, in the range of 54% to 66%, across the different combination dose groups.[24]

The relationship between drug exposure and the reduction in steatosis has been further characterized through exposure-response modeling. This modeling work, incorporating data from both MRI-PDFF and FibroScan® Controlled Attenuation Parameter (CAP™) measurements, supports the observed dose-dependent effect of ervogastat, with or without clesacostat, on reducing liver fat.[39]

While the consistent and significant reduction of hepatic steatosis by ervogastat is a positive pharmacodynamic outcome and addresses an initial pathogenic event in MASH [35], the ultimate measure of its clinical utility hinges on whether this effect translates into meaningful improvements in the downstream histological consequences of the disease, namely inflammation (steatohepatitis) and fibrosis. The progression from steatosis to steatohepatitis and then to advancing fibrosis is complex, and not all agents that reduce liver fat necessarily impact these more clinically critical features. Therefore, the histological data from the MIRNA trial are eagerly awaited to determine if ervogastat can indeed modify the course of MASH beyond steatosis reduction.

5.2. Effects on Histological Markers of NASH and Fibrosis

The true therapeutic potential of any MASH drug candidate lies in its ability to favorably alter the underlying liver histology, specifically by resolving steatohepatitis and/or improving or preventing the progression of liver fibrosis. These histological improvements are considered key indicators of disease modification and are central to regulatory approval.

The Phase 2b MIRNA trial (NCT04321031) was specifically designed to evaluate these critical histological outcomes. The primary endpoint of this 48-week study is a composite measure: the proportion of participants who achieve either resolution of NASH (defined by specific criteria on the NAFLD Activity Score components of inflammation and ballooning) without any worsening of their existing liver fibrosis, OR an improvement in liver fibrosis by at least one stage (according to the NASH Clinical Research Network fibrosis staging system) without any worsening of NASH, OR both of these outcomes concurrently.[5]

In addition to this composite primary endpoint, the MIRNA trial includes several important secondary histological endpoints. These are designed to provide a more granular understanding of the drug's effects and include: the proportion of participants achieving NASH resolution alone (without worsening fibrosis), the proportion achieving fibrosis improvement of ≥1 stage alone (without worsening NASH), the proportion achieving a more substantial fibrosis improvement of ≥2 stages (without worsening NASH), and the proportion achieving an improvement of ≥2 points in the total NAFLD Activity Score (NAS).[8]

As of the latest available information, the detailed results pertaining to these histological endpoints from the completed MIRNA trial have not yet been publicly disclosed. These data are highly anticipated by the medical and scientific community, as they will be crucial in assessing ervogastat's potential to modify the natural history of MASH, particularly in patients with established F2-F3 fibrosis.[4] Positive findings on these histological measures would represent a significant step forward for ervogastat's development program.

5.3. Effects on Metabolic Parameters (Triglycerides, other lipids, glycemic control)

Beyond its effects on liver fat, ervogastat's impact on systemic metabolic parameters, particularly lipids, has been a focus of clinical investigation.

• Serum Triglycerides: Ervogastat monotherapy demonstrated an ability to induce dose-dependent reductions in serum triglyceride levels in early studies involving NAFLD patients.25 This effect is consistent with its mechanism of inhibiting DGAT2, the enzyme responsible for the final step in triglyceride synthesis. A particularly significant finding emerged from the Phase 2a study (NCT03776175) regarding the combination of ervogastat with clesacostat, an ACC inhibitor. ACC inhibitors, while effective at reducing de novo lipogenesis and liver fat, are known to cause an elevation in serum triglycerides as a class effect. The NCT03776175 study showed that the co-administration of ervogastat successfully mitigated this clesacostat-induced hypertriglyceridemia.6 This is a crucial pharmacological advantage, as it suggests that the combination therapy can harness the benefits of ACC inhibition while counteracting one of its main metabolic drawbacks. This synergistic interaction addresses a key limitation of ACC inhibitors as a monotherapy and enhances the appeal of the dual-mechanism approach for MASH.
• Other Lipids: The NCT03776175 study also assessed the effects of ervogastat (monotherapy and combination) on other lipid parameters, including total cholesterol, HDL-cholesterol (HDL-C), and LDL-cholesterol (LDL-C). The results for these were presented as least squares mean (LSM) changes with 90% confidence intervals, relative to placebo.[28] The specific directional changes and magnitudes for each treatment arm would require reference to the full publication of the study.
• Glycemic Control: Some of the NAFLD/NASH clinical trials involving ervogastat included patients with type 2 diabetes mellitus (T2DM).[23] However, the provided research snippets do not contain detailed information specifically on ervogastat's effects on glycemic control parameters (e.g., HbA1c, fasting glucose). While ACC inhibitors like clesacostat have been reported to have some effects on HbA1c [40], the direct impact of ervogastat on glucose metabolism is less clearly defined in the available summaries.

The use of non-invasive imaging techniques like MRI-PDFF and FibroScan CAP for assessing steatosis in the earlier phase trials [8] aligns with current practices in MASH drug development. These tools are valuable for tracking longitudinal changes in liver fat. However, the reliance on liver biopsy for definitive efficacy assessment in the later-stage Phase 2b MIRNA trial underscores the existing regulatory landscape. While NITs are improving, liver histology remains the gold standard for measuring inflammation and fibrosis stage, which are key for MASH diagnosis and staging.[39] The MIRNA trial's design, incorporating biopsy for primary endpoints alongside imaging substudies [8], reflects this reality. Future success in correlating changes observed with NITs to meaningful histological outcomes could eventually lead to broader acceptance and use of NITs as primary endpoints in MASH clinical trials, reducing the need for invasive biopsies.

6. Integrated Safety and Tolerability Analysis

6.1. Overview of Safety Profile

Based on data from early-phase clinical trials, ervogastat has generally been reported as well-tolerated, both when administered as a monotherapy and when co-administered with the ACC inhibitor clesacostat.[4]

In the Phase 2a study NCT03776175, which evaluated ervogastat alone and in combination with clesacostat for 6 weeks in NAFLD patients, adverse events (AEs) were reported in 36% (10 out of 28) of patients receiving the combination therapy. Notably, there were no discontinuations from the study due to AEs in this combination arm, which is a positive indicator of tolerability.[28]

A plain language summary for a related Phase 2a study, NCT03711005 (also C3711005), which assessed different doses of ervogastat in combination with clesacostat for 6 weeks in participants with presumed NASH, indicated that the most commonly reported medical problems were diarrhea, headache, and nausea. Serious medical problems were reported as infrequent in this study.[24] The plain language summary for NCT03776175 (referred to as C3711001 in that document) also generally suggested that the combination "may be an option," implying acceptable tolerability.[23]

While these early findings are encouraging, it is important to note that detailed breakdowns of adverse events, particularly for ervogastat monotherapy arms in Phase 2a studies, are not extensively provided in the summarized snippets available.[28] A more comprehensive understanding of ervogastat's long-term safety and tolerability profile will emerge from the analysis of the larger and longer-duration Phase 2b MIRNA trial (NCT04321031), which included systematic collection of TEAEs, laboratory parameters, vital signs, and ECGs over a 48-week treatment period.[33] The safety data from MIRNA and any subsequent Phase 3 trials will be crucial, as MASH is a chronic condition requiring prolonged therapy, making long-term safety a paramount consideration.

6.2. Common and Serious Adverse Events (AEs)

Specific details on common and serious adverse events are somewhat limited in the provided summaries, particularly for ervogastat monotherapy.

• Phase 2a Study (NCT03711005 - Ervogastat + Clesacostat combinations): The plain language summary for this 6-week study in participants with presumed NASH identified the most common AEs (occurring in ≥5% of participants in any group) as diarrhea, headache, and nausea.[24] Regarding serious adverse events (SAEs), one participant in the placebo group experienced an SAE (worsening of anxiety). Crucially, no SAEs were reported in any of the active treatment groups receiving ervogastat in combination with clesacostat in this particular study.[24]

Comprehensive adverse event tables that compare ervogastat monotherapy directly against combination therapy and placebo from the NCT03776175 study would necessitate access to the full peer-reviewed publication.[28] The safety results from the much larger and longer (48-week) Phase 2b MIRNA trial (NCT04321031) are anticipated to provide a more robust characterization of both common and potentially rarer adverse events associated with longer-term exposure to ervogastat.

6.3. Discontinuation Rates

Information on discontinuation rates due to adverse events provides insight into the overall tolerability of a drug.

• In the Phase 2a study NCT03776175, it was reported that there were no discontinuations due to AEs in the arm receiving the combination of ervogastat and clesacostat.[28] This is a favorable finding, suggesting good tolerability of the combination over the 6-week treatment period.
• In the Phase 2a study NCT03711005, the plain language summary mentioned that 4 out of 74 participants who started the study left before its completion by their own choice. The summary does not explicitly state that these discontinuations were due to adverse events.[24]

Data on discontinuation rates specifically from ervogastat monotherapy arms in these studies are not clearly delineated in the available snippets. The results from the MIRNA trial will be important for understanding discontinuation rates with longer-term treatment across different doses and in monotherapy versus combination settings.

6.4. Specific Safety Considerations

Several specific safety aspects warrant consideration based on ervogastat's mechanism of action and preclinical findings:

• Developmental Toxicity: Preclinical studies in rats revealed developmental effects when ervogastat was administered during organogenesis (reduced fetal weight, transient bent bones) and more significantly with extended dosing through gestation and lactation (impaired skin development, reduced offspring viability, growth retardation).[20] These findings are attributed to the drug's primary pharmacological effect—alteration of triglyceride metabolism, which is essential for normal development. Consequently, clinical trials involving ervogastat have typically excluded pregnant women and women of childbearing potential not using effective contraception. If ervogastat were to reach the market, careful risk management strategies, including potential contraindications or stringent warnings for use during pregnancy and breastfeeding, and requirements for effective contraception, would be expected, aligning with standard practice for drugs with such preclinical developmental signals.
• Gastrointestinal Tolerability: Theoretically, selective DGAT2 inhibition is anticipated to offer better gastrointestinal (GI) tolerability compared to DGAT1 inhibition, due to the predominant hepatic expression of DGAT2 versus the intestinal expression of DGAT1.[29] Some reviews have noted ervogastat's efficacy on liver steatosis "without serious gastrointestinal adverse events".[12] However, in the NCT03711005 combination study, diarrhea and nausea were among the most commonly reported AEs.[24] The overall GI safety profile with longer-term use will be further clarified by the MIRNA trial data.
• Metabolic Effects: While a key advantage of combining ervogastat with an ACC inhibitor like clesacostat is the mitigation of ACCi-induced hypertriglyceridemia [6], ongoing monitoring of the full lipid profile and other metabolic parameters (e.g., glucose homeostasis) remains an important aspect of its clinical evaluation, especially in a MASH population often characterized by multiple metabolic derangements.
• Drug-Drug Interactions: Ervogastat's metabolism via CYP3A and its potential to induce CYP3A, along with its role as a substrate and potential inhibitor of P-gp and BCRP transporters, indicate a susceptibility to drug-drug interactions (DDIs).[27] Given that MASH patients frequently have comorbidities like type 2 diabetes, hypertension, and dyslipidemia, and are therefore often on multiple medications [23], the potential for DDIs is a significant clinical consideration. While the DDI study with clesacostat (NCT03534648) did not show clinically meaningful PK interactions for that specific pairing [27], a broader assessment of DDI potential and clear guidance for co-medication management will be essential for safe clinical use.

7. Regulatory Status and Future Outlook

7.1. FDA Fast Track Designation

A significant regulatory milestone for the ervogastat program was the granting of Fast Track designation by the U.S. Food and Drug Administration (FDA). This designation was specifically awarded to the investigational combination therapy comprising ervogastat (PF-06865571) and clesacostat (PF-05221304) for the treatment of NASH with liver fibrosis.[4]

The FDA's decision to grant Fast Track status was informed by the results from Pfizer's nonclinical studies and, notably, a Phase 2a clinical study (likely NCT03776175) which demonstrated that treatment with the ervogastat/clesacostat combination effectively reduced liver fat while maintaining a favorable safety and tolerability profile.[4] The Fast Track program is designed to facilitate the development and expedite the review of drugs intended to treat serious conditions and fill an unmet medical need. This designation for the combination therapy underscores the FDA's recognition of its potential to address the significant therapeutic gap in NASH, particularly for patients with liver fibrosis. While the available information clearly indicates Fast Track for the combination, it is not explicitly stated that ervogastat monotherapy received a similar designation. This may suggest that both Pfizer and regulatory bodies perceive the combination as holding greater promise for tackling the complexities of NASH with fibrosis, possibly due to the dual mechanism of action and the mitigation of ACC inhibitor-related side effects.

7.2. Potential Role in NASH/MASH Management

Ervogastat, particularly when used in combination with clesacostat, holds the potential to become a valuable therapeutic option for MASH. Its primary mechanism of reducing hepatic steatosis by inhibiting DGAT2 directly targets a core pathological process in the disease.[4] Furthermore, the ability of ervogastat to counteract the hypertriglyceridemia associated with ACC inhibitors like clesacostat makes the combination approach particularly compelling from both an efficacy and safety standpoint.[6]

If the Phase 2b MIRNA trial successfully demonstrates significant histological improvements—namely, resolution of steatohepatitis and/or regression of fibrosis—ervogastat could play an important role in future MASH treatment paradigms. This is especially relevant given the historical lack of approved therapies for the more advanced, fibrotic stages of the disease. The recent approval of Rezdiffra (resmetirom) for non-cirrhotic MASH with F2-F3 fibrosis [13] has begun to change this landscape, but the need for multiple effective agents with different mechanisms remains high.

7.3. Future Clinical Development Plans

The clinical development trajectory for ervogastat is heavily contingent on the outcomes of the Phase 2b MIRNA trial (NCT04321031). This study, which completed in early 2024, was designed to provide robust data on histological endpoints, and its results are expected to inform the decision-making process for a potential Phase 3 development program, likely focusing on the ervogastat/clesacostat combination.[4]

Pfizer's official pipeline updates, as of early 2025, continue to list ervogastat (both as monotherapy and in combination with clesacostat) in Phase 2 for MASH.[15] This status suggests that the analysis of the MIRNA trial data is either ongoing, or that strategic decisions regarding progression to Phase 3 are under active consideration based on these results. The timing of the MIRNA trial's completion relative to the recent approval of Rezdiffra creates a dynamic environment. Positive and compelling results from MIRNA will be essential for Pfizer to effectively position ervogastat, likely as a combination therapy, within a market that now includes an approved agent. Should the MIRNA data be strong, demonstrating comparable or superior efficacy on key histological endpoints along with a favorable safety profile, ervogastat could emerge as a competitive alternative or find utility in specific patient segments or as part of future multi-drug regimens.

Furthermore, reports indicate that Pfizer has also explored the development of an extended-half-life DGAT2 inhibitor.[29] This suggests a long-term strategic commitment to the DGAT2 inhibition mechanism. Such a next-generation compound could offer advantages like improved dosing convenience (e.g., true once-daily dosing for monotherapy if ervogastat's current half-life proves to be a limitation for such a regimen) or an enhanced therapeutic window. This forward-looking approach indicates that Pfizer is not only focused on the immediate development of ervogastat but is also invested in optimizing DGAT2 inhibition as a sustained therapeutic strategy for MASH.

7.4. Comparative Landscape (Brief Mention)

The therapeutic landscape for MASH is dynamic and highly competitive, with numerous investigational agents targeting various pathological pathways.[9] Ervogastat is one of several DGAT2 inhibitors in development; other examples include LG203003 and ION224 (an antisense oligonucleotide targeting DGAT2 mRNA).[12]

The recent FDA approval of Resmetirom (Rezdiffra), a thyroid hormone receptor-beta (THR-β) agonist, for adults with non-cirrhotic MASH and moderate to advanced liver fibrosis (stages F2-F3), marks a watershed moment.[6] This approval not only provides the first MASH-specific therapy but also validates the feasibility of achieving regulatory success based on histological endpoints. It sets a benchmark against which new therapies, including ervogastat, will be compared.

The complexity of MASH pathophysiology increasingly points towards combination therapies as the most promising approach for achieving comprehensive and durable treatment responses.[9] Ervogastat, with its strong rationale for use in combination with an ACC inhibitor, is well-aligned with this evolving therapeutic paradigm.

8. Conclusion

Ervogastat (PF-06865571) has emerged from Pfizer's research pipeline as a potent, selective, and orally administered inhibitor of Diacylglycerol O-Acyltransferase 2 (DGAT2). Its development has been primarily focused on addressing the significant unmet medical need in Metabolic Dysfunction-Associated Steatohepatitis (MASH), particularly in patients with liver fibrosis. The core mechanism of action, inhibition of triglyceride synthesis, directly targets hepatic steatosis, a foundational element in the pathogenesis of MASH.

Key efficacy findings from Phase 1 and Phase 2a clinical trials have consistently demonstrated ervogastat's ability to reduce liver fat content in individuals with NAFLD and MASH, both as a monotherapy and, more notably, in combination with the ACC inhibitor clesacostat. A particularly compelling attribute of the combination therapy is ervogastat's capacity to mitigate the hypertriglyceridemia often associated with ACC inhibition, thereby potentially offering a more favorable metabolic profile for the dual-mechanism approach. This journey underscores a significant trend in MASH drug development: the strategic move towards combination therapies that target multiple pathogenic pathways. Such an approach aims not only to achieve more profound histological improvements but also to manage mechanism-based side effects, reflecting a nuanced understanding of MASH's complex nature.

The safety profile of ervogastat observed in these earlier, shorter-term studies has generally been reported as favorable, with manageable adverse events. However, preclinical developmental toxicity findings necessitate careful consideration for its use in women of childbearing potential. The comprehensive safety and efficacy data from the recently completed 48-week Phase 2b MIRNA trial (NCT04321031) are now paramount. The results from MIRNA, especially the effects on histological endpoints such as NASH resolution and fibrosis regression, will be critical in defining ervogastat's future role and its potential to modify the course of MASH.

The success of ervogastat, particularly if the MIRNA trial yields positive histological outcomes, could significantly validate DGAT2 as a druggable target for MASH. Such validation from a major pharmaceutical entity often de-risks the target for the broader scientific community, potentially spurring further investment and research into this specific mechanism beyond Pfizer's own pipeline and fostering the development of more therapeutic options.

The regulatory path forward, especially if pursued as a combination therapy, will be closely observed. The FDA's Fast Track designation for the ervogastat/clesacostat combination is an encouraging sign. However, navigating the approval process for a combination product, where one or both components may not be independently approved as monotherapies for MASH, presents unique regulatory considerations and may set precedents for future MASH combination therapies.

In conclusion, ervogastat (PF-06865571) stands as a promising investigational agent. Its development program, characterized by a rational design approach and a strategic focus on combination therapy, positions it as a potentially valuable contributor to the evolving MASH treatment landscape. The forthcoming detailed results from the MIRNA trial will be instrumental in determining its ultimate clinical utility and its ability to address the pressing needs of patients suffering from this progressive liver disease.

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