Efinopegdutide (MK-6024): A Comprehensive Profile of an Investigational Dual GLP-1/Glucagon Receptor Agonist for Metabolic Liver Disease

I. Introduction to Efinopegdutide (MK-6024)

A. Overview

Efinopegdutide is an investigational biopharmaceutical agent currently undergoing clinical evaluation, primarily for the treatment of metabolic liver diseases such as nonalcoholic steatohepatitis (NASH), a condition increasingly referred to as metabolic dysfunction-associated steatohepatitis (MASH).[1] It represents a novel therapeutic approach based on its mechanism as a potent dual agonist targeting both the glucagon-like peptide-1 receptor (GLP-1R) and the glucagon receptor (GCGR).[4] This dual agonism is hypothesized to confer specific advantages in managing the complex pathophysiology of NASH/MASH, potentially offering greater efficacy in reducing liver fat and inflammation compared to therapies targeting only the GLP-1 pathway.[5]

The development trajectory of Efinopegdutide has involved multiple pharmaceutical entities, reflected in its various identifiers throughout its history. This suggests a complex path influenced by shifting strategic priorities and evolving assessments of the drug's therapeutic potential across different indications.[4] The consistent emphasis on its dual GLP-1/Glucagon mechanism, however, underscores this feature as the central scientific rationale driving its current development focus on liver disease.[4]

B. Identification

The compound is internationally recognized by the nonproprietary name Efinopegdutide. Key identifiers used during its development and within scientific databases include:

• DrugBank Accession Number: DB15077 [1]
• CAS Registry Number: 2055640-93-0 [10]
• Development Codes/Synonyms:
• MK-6024 (Merck Sharp & Dohme) [4]
• JNJ-64565111 (Janssen Research & Development) [6]
• HM12525A (Hanmi Pharmaceutical) [6]
• LAPS-GLP/GCG [33]
• UNII (FDA Unique Ingredient Identifier): DR6P1M58PO [28]
• WHO Number (INN): 10793 [28]
• USAN File Number: GH-23 [28]

C. Development Context

Efinopegdutide has progressed through standard early-phase clinical safety assessments. An initial background study mentioned in its DrugBank profile is NCT03606057, a Phase 1 thorough QT/QTc trial designed to investigate the potential effect of JNJ-64565111 (an earlier code for Efinopegdutide) on cardiac repolarization in healthy adults, comparing it against placebo and a positive control, moxifloxacin.[32] The conduct of such a study is a routine regulatory requirement for many new drug candidates to rule out significant risks of cardiac arrhythmias.

II. Chemical Properties and Structure

A. Drug Classification

Efinopegdutide is classified as a Biotech drug.[32] More specifically, it is characterized structurally as a Fusion Protein.[9]

B. Structural Composition

The molecule is a complex conjugate engineered by combining distinct biological components to achieve desired pharmacological properties, particularly an extended duration of action suitable for once-weekly administration.[4] Its structure comprises:

1. Peptide Moiety: An analogue of oxyntomodulin, a naturally occurring peptide hormone known to possess dual agonist activity at both GLP-1 and glucagon receptors.[28] Specific amino acid substitutions within the peptide sequence (detailed in the USAN statement, including modifications like S2''>B, S16''>E, R17''>K, Q20''>K, D21''>E, K30''>C) are likely incorporated to optimize receptor binding affinities, potency, selectivity, and metabolic stability compared to the native peptide.[28] The peptide component features a C-terminal amide.[28]
2. Protein Moiety: A dimer of the Fc fragment derived from human Immunoglobulin G4 (IgG4).[28] The sequence origin is confirmed as human.[31] Fusion to an Fc fragment is a common strategy to extend the plasma half-life of therapeutic peptides and proteins by utilizing the neonatal Fc receptor (FcRn) recycling pathway, which protects IgG molecules from lysosomal degradation.
3. Linker: A polyethylene glycol (PEG) linker connects the peptide moiety to the IgG4 Fc dimer.[28] The PEG linker is described as approximately 10 kDa in size, corresponding to an average chain length (n) of about 225 oxyethylene units.[28] PEGylation increases the hydrodynamic size of the molecule, reducing renal clearance and potentially shielding the peptide from proteolytic degradation, further contributing to its extended half-life.

C. Subunit Details

Structural databases indicate Efinopegdutide consists of multiple subunits.[31] Based on the USAN statement and database entries, this includes [28]:

• Subunit 1 & 2: Two identical polypeptide chains representing the human IgG4 Fc fragment (residues 9-229, linked by disulfide bonds). The sequence provided is: PSCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK.
• Subunit 3: The modified oxyntomodulin analogue peptide sequence: HAQGTFTSDYSKYLDEKRAKEFVQWLMNTC-NH2. The USAN document notes specific modifications (S2''>B, S16''>E, R17''>K, Q20''>K, D21''>E, K30''>C) and a cyclic amide structure involving residues 16 and 20 (lactam bridge), along with conjugation via the C-terminal Cys30 to the PEG linker attached to the Fc fragments.[28]

D. Molecular Weight

The approximate molecular weight of the entire fusion protein conjugate is reported as 63.60 kDa.[28] This value is consistent with the combined mass of the dimerized IgG4 Fc fragment (approximately 50 kDa), the peptide moiety, and the ~10 kDa PEG linker. It should be noted that some database sources list the molecular weight as not available (N/A) [12], which may reflect the inherent heterogeneity (polydispersity) of PEGylated molecules, making precise molecular weight determination challenging. However, the USAN document provides the most authoritative available value.[28]

E. Chemical Name (Systematic)

The formal chemical name reflects the complex structure, incorporating the peptide sequence, the PEG linker, and the IgG4 Fc fragment. A representative, though potentially truncated, version is: Poly(oxy-1,2-ethanediyl), α-hydro-ω-hydroxy-, α30-ether with -L-histidyl-2-methylalanyl-L-glutaminylglycyl-L-threonyl-L-phenylalanyl-L-threonyl-L-seryl-L-α-aspartyl-L-tyrosyl-L-seryl-L-lysyl-L-tyrosyl-L-leucyl-L-α-aspartyl-L-α-glutamyl-L-lysyl-L-arginyl-L-alanyl-L-lysyl-L-α-glutamyl-L-phenylalanyl-L-valyl-L-glutaminyl-... (peptide sequence continues)...-L-cysteinamide (16→20)-lactam, ω1-ether with immunoglobulin G4 [1-(3-hydroxypropyl)proline]](human Fc fragment), (3→3')-disulfide with immunoglobulin G4 (human Fc fragment).[28]

Table 1: Efinopegdutide Identification and Chemical Properties

Feature	Detail	Source Snippet(s)
Nonproprietary Name	Efinopegdutide	4
DrugBank ID	DB15077	1
CAS Number	2055640-93-0	10
UNII	DR6P1M58PO	28
WHO Number	10793	28
USAN File Number	GH-23	28
Other Codes/Synonyms	MK-6024, JNJ-64565111, HM12525A, LAPS-GLP/GCG	4
Drug Type	Biotech, Fusion Protein	9
Structural Components	Oxyntomodulin analogue peptide, Human IgG4 Fc fragment (dimer), Polyethylene glycol (PEG) linker (~10 kDa)	28
Molecular Weight	~63.60 kDa	28

III. Mechanism of Action and Pharmacological Profile

A. Primary Mechanism

The fundamental mechanism of action of Efinopegdutide is its function as a potent dual agonist that simultaneously activates two distinct G-protein coupled receptors (GPCRs): the Glucagon-like peptide-1 receptor (GLP-1R) and the Glucagon receptor (GCGR).[4] This dual agonism is the cornerstone of its therapeutic rationale, particularly for complex metabolic disorders involving the liver.

B. Biological Targets

The primary molecular targets have been explicitly identified as:

• Glucagon-like peptide 1 receptor (GLP-1R): Targeted with agonist action. (ChEMBL ID: CHEMBL1784).[9]
• Glucagon receptor (GCGR): Targeted with agonist action. (ChEMBL ID: CHEMBL1985).[9]

C. Rationale for Dual Agonism in Metabolic Disease

The strategy of combining GLP-1R and GCGR agonism aims to harness the beneficial effects of both pathways while potentially achieving synergistic outcomes, especially relevant for NASH/MASH:

• GLP-1 Receptor Activation: Contributes well-established metabolic benefits, including glucose-dependent insulin secretion, suppression of glucagon release, delayed gastric emptying leading to reduced postprandial glucose excursions, central nervous system effects promoting satiety and appetite reduction, and consequent weight loss.[5] Weight loss itself is a key factor in improving liver histology in NAFLD/NASH.[15]
• Glucagon Receptor Activation: While traditionally known for increasing blood glucose via hepatic glucose production (gluconeogenesis and glycogenolysis) [52], glucagon signaling is also implicated in other metabolic effects relevant to NASH. These include potentially increasing energy expenditure, stimulating hepatic fatty acid oxidation, and reducing de novo lipogenesis (fat synthesis) in the liver.[5] Glucagon may also contribute to satiety and weight regulation.[48]
• Therapeutic Hypothesis for NASH/MASH: The core rationale for developing Efinopegdutide for NASH rests on the hypothesis that GCGR agonism provides a direct beneficial effect on the liver pathology (reducing steatosis and potentially inflammation/fibrosis drivers by altering lipid metabolism) that complements the indirect benefits derived from GLP-1R-mediated weight loss.[5] Experimental evidence suggests potential synergy between GLP-1 and glucagon signaling pathways on energy balance.[16] This combined approach aims to achieve greater improvements in liver health, particularly liver fat reduction, than what can be attained with GLP-1R agonism alone.[5] Clinical data from the Phase 2a NAFLD trial, demonstrating superior liver fat reduction compared to semaglutide despite similar weight loss, lends support to this hypothesis.[15]

However, balancing the opposing effects of GLP-1 (glucose-lowering) and glucagon (glucose-raising) presents a pharmacological challenge.[25] The net effect on glycemic control can be complex and context-dependent. Results from a Phase 2 trial in patients with Type 2 Diabetes Mellitus (T2DM) showed significant weight loss but failed to demonstrate improvements in HbA1c, and even showed numerical increases in fasting glucose and insulin at some doses.[25] This outcome highlights the potential counteractive effects on glucose metabolism and likely explains the discontinuation of development for T2DM and obesity indications, where optimizing glycemic control and maximizing weight loss without adverse metabolic consequences are primary goals. For NASH, particularly in non-diabetic individuals or those with well-controlled T2DM, the anticipated direct liver benefits might be considered to outweigh potential minor impacts on glucose homeostasis.[5]

D. Pharmacokinetics (PK)

Detailed pharmacokinetic data for Efinopegdutide (such as absorption rate, volume of distribution, specific metabolic pathways, excretion routes, and precise half-life) are largely unavailable in the public domain, as explicitly noted by sources like DrugBank.[32]

However, several key aspects can be inferred or are known:

• Administration and Half-life: Efinopegdutide is administered via subcutaneous injection, typically on a once-weekly schedule in clinical trials.[4] This dosing interval is enabled by its molecular design, specifically the fusion to an IgG4 Fc fragment and conjugation with a PEG linker, both established strategies known to significantly prolong the plasma half-life of peptide therapeutics.[28]
• Assessment in Trials: PK parameters were formally assessed as objectives in several clinical trials, including the terminated Phase 1 study in T2DM (NCT02862431) [44] and the completed Phase 1 study in participants with hepatic impairment (NCT06052566).[1] PK assessments are also likely integral to other early-phase and ongoing studies, such as the alternate dosing trial (NCT06482112).[6]
• Metabolism and Elimination: As a large peptide-protein conjugate, Efinopegdutide is expected to be metabolized primarily through proteolytic degradation into smaller peptides and amino acids, which are then recycled or eliminated. The IgG Fc portion would likely be catabolized through pathways typical for immunoglobulins. This contrasts with the hepatic cytochrome P450 (CYP450) enzyme system metabolism common for small-molecule drugs. Specific details on the metabolic fate and route of elimination are not provided in the available sources.[32]

The absence of detailed public PK data limits a full understanding of the exposure-response relationships and potential variability between patient populations. Ongoing studies, particularly the alternate dosing trial [39], are likely aimed at further characterizing these aspects to optimize the therapeutic regimen.

E. Pharmacodynamics (PD)

Similar to pharmacokinetics, specific pharmacodynamic parameters beyond the mechanism of action are generally reported as "Not Available" in public databases.[32] PD effects, such as the magnitude and time course of changes in liver fat, body weight, glucose levels, and other biomarkers, are primarily inferred from the efficacy and safety results reported in clinical trials (see Sections V and VI).

PD assessments were included as objectives in specific studies:

• The terminated Phase 1 T2DM trial (NCT02862431) aimed to assess PD effects.[44]
• The thorough QT study (NCT03606057) specifically evaluated the pharmacodynamic effect on the QTc interval as a measure of cardiac safety.[32]

Without more detailed PD modeling data, fully characterizing the dose-dependent effects on various physiological parameters remains challenging based solely on the provided information.

IV. Clinical Development Program

A. Development History and Sponsorship

Efinopegdutide's clinical development has been shaped by transitions between pharmaceutical companies:

• Origination: The compound originated at Hanmi Pharmaceutical Co., Ltd. under the code HM12525A.[9]
• Janssen Phase: Hanmi licensed the drug to Janssen Research & Development, LLC (a Johnson & Johnson company), where it was assigned the code JNJ-64565111.[9] During this period, clinical development primarily focused on indications of obesity and Type 2 Diabetes Mellitus (T2DM).[9]
• Janssen Discontinuation: Janssen subsequently discontinued its development program for JNJ-64565111 and returned the rights to Hanmi. Reports suggest this decision was made after Phase 2 obesity trials, possibly because the results did not meet internal benchmarks or align with Janssen's strategic focus in the rapidly evolving metabolic disease landscape.[9]
• Merck Phase: In August 2020, Merck Sharp & Dohme LLC (Merck & Co., Inc.) acquired exclusive global development, manufacturing, and commercialization rights (excluding Korea) from Hanmi.[4] The licensing deal involved an upfront payment of $10 million and potential future milestone payments up to $860 million.[17] Under Merck, the compound was designated MK-6024, and the development strategy pivoted decisively towards NASH/MASH.[4] Hanmi retains commercialization rights in Korea.[29]

This transition from Janssen (focusing on obesity/T2DM) to Merck (focusing on NASH) marks a significant strategic redirection. It likely reflects Merck's recognition of the high unmet medical need in NASH and an assessment that Efinopegdutide's unique dual mechanism, particularly its potential for direct liver effects, offered a competitive advantage in this specific therapeutic area. This may have been influenced by Janssen's evaluation of the drug's competitiveness against other emerging GLP-1-based therapies in the crowded obesity and T2DM markets.[21]

B. Investigated Indications & Trial Status Overview

Efinopegdutide has been investigated across a range of metabolic conditions, with a clear shift in focus over time:

• Primary Active Development Focus (Merck):
• Nonalcoholic Steatohepatitis (NASH) / Metabolic Dysfunction-associated Steatohepatitis (MASH): Currently the lead indication. Phase 2b trials are ongoing.[2]
• Nonalcoholic Fatty Liver Disease (NAFLD) / Metabolic Dysfunction-associated Steatotic Liver Disease (MASLD): A Phase 2a trial (NCT04944992) has been completed.[1] A Phase 2 alternate dosing study (NCT06482112) in MASLD is currently recruiting.[39]
• Liver Cirrhosis: A Phase 2 trial (NCT06465186) is recruiting patients with compensated cirrhosis due to MASH.[3]
• Discontinued/Terminated Indications (Primarily Janssen):
• Obesity: Phase 2 development was completed (NCT03486392) but the indication was subsequently discontinued.[9]
• Type 2 Diabetes Mellitus (T2DM): A Phase 1 trial (NCT02862431) was terminated.[44] A Phase 2 trial was completed [25], but development for T2DM as a primary indication was discontinued.[9] The termination of the Phase 1 T2DM trial and the lack of efficacy on glycemic control in the Phase 2 T2DM study provide strong evidence supporting the strategic shift away from this indication.[25]
• Supportive/Safety Studies:
• Cardiac Safety (QTc Interval): A Phase 1 thorough QT study (NCT03606057) was completed.[32]
• Hepatic Impairment: A Phase 1 study (NCT06052566) in participants with varying degrees of hepatic impairment has been completed.[1]

The clinical program under Merck demonstrates a focused and logical progression within liver disease. Starting with proof-of-concept in NAFLD using liver fat content (LFC) as a biomarker endpoint [15], development has advanced to Phase 2b trials in biopsy-confirmed pre-cirrhotic NASH, targeting regulatory-relevant histological endpoints (NASH resolution, fibrosis improvement).[4] Expansion into the MASH patient population with compensated cirrhosis addresses a group with significant unmet medical need.[3] Furthermore, the initiation of an alternate dosing regimen study indicates ongoing efforts to optimize treatment delivery and potentially improve tolerability or convenience.[39]

C. Key Clinical Trials

Table 2: Summary of Key Efinopegdutide Clinical Trials

Identifier(s)	Phase	Status	Indication(s)	Key Design / Comparator(s)	Primary Outcome(s) / Brief Result Summary	Sponsor (at time of trial)	Source Snippet(s)
NCT04944992 / EudraCT 2020-005136-30	2a	Completed	NAFLD (incl. T2DM subset)	Open-label, Active-controlled; Efinopegdutide 10mg QW vs. Semaglutide 1mg QW; 24 weeks	% change LFC at Wk 24. Result: Efinopegdutide superior to Semaglutide (-72.7% vs -42.3%, p<0.001)	Merck	2
NCT05877547 / IRAS 1007627	2b	Active, not recruiting / Ongoing	Precirrhotic NASH (biopsy-confirmed)	Randomized, Double-blind, Placebo-controlled; Efinopegdutide (4, 7, 10mg QW) vs Placebo; Open-label Semaglutide 2.4mg arm (UK); 52 weeks	Histological improvement (NASH resolution or fibrosis improvement)	Merck	4
NCT06465186	2	Recruiting	MASH with Compensated Cirrhosis	Randomized, Placebo-controlled; Efinopegdutide vs Placebo; 28 weeks	Safety, Tolerability, Efficacy (liver fat, inflammation, fibrosis markers)	Merck	3
NCT06482112 / EU CT 2024-510923-20-00	2	Recruiting	MASLD	Randomized; Efinopegdutide Q2W vs Q1W; 28 weeks	% change LFC at Wk 28, Safety, Tolerability	Merck	18
NCT03486392	2	Completed	Obesity (non-diabetic, severe)	Randomized, Double-blind, Placebo & Active-controlled; Efinopegdutide (5, 7.4, 10mg QW) vs Placebo vs Liraglutide 3mg QW; 26 weeks	% change body weight at Wk 26. Result: Dose-dependent weight loss, superior to Placebo & Liraglutide	Janssen	9
Ref: 25	2	Completed	T2DM with Obesity	Randomized, Double-blind, Placebo-controlled; Efinopegdutide (5, 7.4, 10mg QW) vs Placebo; 12 weeks	% change body weight at Wk 12. Result: Dose-dependent weight loss vs Placebo; No HbA1c improvement	Janssen	25
NCT02862431 / EudraCT 2016-001084-37	1	Terminated	T2DM	Randomized, Placebo-controlled; Dose escalation	Safety, Tolerability, PK, PD	Janssen	44
NCT03606057	1	Completed	Healthy Adults	Randomized, Placebo & Active-controlled (Moxifloxacin); Single dose	Effect on QTc interval	Janssen	32
NCT06052566	1	Completed	Hepatic Impairment	Open-label; Single dose	PK in hepatic impairment	Merck	1

(LFC = Liver Fat Content; QW = Once Weekly; Q2W = Once Every 2 Weeks; PK = Pharmacokinetics; PD = Pharmacodynamics)

V. Clinical Efficacy Findings

Clinical trials have evaluated Efinopegdutide's efficacy across several metabolic indications, yielding distinct results that have shaped its development path.

A. Phase 2a Nonalcoholic Fatty Liver Disease (NAFLD) Study (NCT04944992)

This key study compared Efinopegdutide 10mg administered subcutaneously once weekly (QW) against the active comparator Semaglutide 1mg QW over 24 weeks in 145 participants with NAFLD (defined as liver fat content [LFC] ≥10% via MRI-PDFF), approximately one-third of whom also had T2DM.[15]

• Liver Fat Content Reduction (Primary Endpoint): Efinopegdutide demonstrated statistically significant superiority over Semaglutide in reducing LFC. The least squares (LS) mean relative reduction from baseline at Week 24 was -72.7% for Efinopegdutide versus -42.3% for Semaglutide, representing a difference of -30.4% (90% CI -38.7 to -22.1; p < 0.001).[15] Median relative LFC reduction also favored Efinopegdutide (-83.8% vs -44.4%).[24] This pronounced effect on liver fat is the most compelling efficacy signal observed for Efinopegdutide.
• LFC Responder Analysis: Significantly higher proportions of patients treated with Efinopegdutide achieved clinically relevant thresholds of LFC reduction compared to Semaglutide [5]:
• ≥30% LFC reduction (threshold associated with histologic benefit): 81.9% vs 67.1%
• ≥50% LFC reduction: 77.8% vs 43.8%
• ≥70% LFC reduction ("super responders"): 70.8% vs 12.3%
• LFC normalization (<5%): 66.7% vs 17.8%
• Weight Loss: Both treatments resulted in weight loss. The LS mean percent reduction from baseline body weight at Week 24 was -8.5% for Efinopegdutide and -7.1% for Semaglutide. While numerically greater for Efinopegdutide, this difference did not reach statistical significance (p = 0.085).[15] The superior LFC reduction achieved by Efinopegdutide in the absence of significantly greater weight loss strongly supports the hypothesis of a direct hepatic effect mediated by glucagon receptor agonism, beyond the indirect benefits of weight reduction.[5]
• Subgroup Analysis (T2DM): Post-hoc analyses indicated that the substantial reductions in LFC observed with both Efinopegdutide and Semaglutide were similar in participants with and without T2DM. This suggests that the presence of diabetes did not attenuate the beneficial effect of Efinopegdutide on liver fat, alleviating potential concerns about the glucagon component's impact in this subgroup.[5]
• Liver Enzymes: Reductions in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were observed in both groups, with similar magnitudes of decline.[24]

B. Phase 2 Obesity Study (NCT03486392)

This study evaluated three doses of Efinopegdutide (5.0mg, 7.4mg, 10.0mg QW) against placebo and the active comparator Liraglutide 3.0mg QW over 26 weeks in individuals with severe obesity (BMI 35-50 kg/m²) but without T2DM.[23]

• Weight Loss (Primary Endpoint): Efinopegdutide produced statistically significant and dose-dependent reductions in body weight compared to placebo. At Week 26, the placebo-subtracted LS mean weight changes were -6.8% (5.0mg dose), -8.1% (7.4mg dose), and -10.0% (10.0mg dose).[23]
• Comparison with Liraglutide: The Liraglutide 3.0mg group achieved a placebo-subtracted weight loss of -5.8%. All tested doses of Efinopegdutide resulted in numerically greater weight loss than Liraglutide 3.0mg.[23] Despite demonstrating potent weight loss effects superior to Liraglutide 3mg, this indication was not pursued further by Merck. This decision might reflect an assessment of the drug's competitiveness against newer, potentially more effective obesity agents entering the market, concerns about its tolerability profile for a broad obesity population, or a strategic prioritization of the NASH indication.[21]

C. Phase 2 Type 2 Diabetes Mellitus (T2DM) Study

A separate Phase 2 study assessed Efinopegdutide (5.0mg, 7.4mg, 10.0mg QW) versus placebo over 12 weeks in individuals with T2DM (HbA1c 6.5%-9.5%) and class II/III obesity.[25]

• Weight Loss: Similar to the obesity study, Efinopegdutide led to significant, dose-dependent weight loss compared to placebo at Week 12 (placebo-subtracted changes: -4.6% for 5.0mg, -5.9% for 7.4mg, -7.2% for 10.0mg).[25]
• Glycemic Control: Critically, despite the substantial weight loss, Efinopegdutide treatment was not associated with any improvement in HbA1c levels compared to placebo. Furthermore, slight numerical increases in fasting plasma glucose and fasting insulin were observed with the 5.0mg and 7.4mg doses.[25] This lack of glycemic benefit, likely due to the counteracting hyperglycemic potential of glucagon agonism, strongly confirmed the unsuitability of Efinopegdutide as a primary treatment for T2DM and reinforced the strategic focus on liver disease, where patient selection might mitigate concerns about glycemic effects.[5]

Table 3: Comparative Efficacy Summary (Phase 2 Studies)

Study (Identifier/Ref)	Indication	Efinopegdutide Dose(s) (QW)	Comparator(s) (QW)	Duration	Primary Endpoint	Efinopegdutide Result	Comparator Result	Key Secondary Results	Significance / P-value	Source Snippet(s)
NCT04944992	NAFLD	10mg	Semaglutide 1mg	24 Weeks	% Change LFC	-72.7% (LS Mean)	-42.3% (LS Mean)	Wt Loss: -8.5% (LS Mean); LFC ≥70% Red.: 70.8%	LFC: p<0.001; Wt Loss: p=0.085	15
NCT03486392	Obesity (non-diabetic)	5mg, 7.4mg, 10mg	Placebo, Liraglutide 3mg	26 Weeks	% Change Body Weight	-6.8%, -8.1%, -10.0% (Placebo-subtracted LS Mean)	Placebo: Baseline; Liraglutide: -5.8% (Placebo-subtracted LS Mean)	N/A in snippets	Wt Loss vs Placebo: Significant (dose-dependent)	23
Ref: 25	T2DM with Obesity	5mg, 7.4mg, 10mg	Placebo	12 Weeks	% Change Body Weight	-4.6%, -5.9%, -7.2% (Placebo-subtracted)	Placebo: Baseline	HbA1c: No change vs Placebo; ↑ FPG/Insulin (5mg, 7.4mg)	Wt Loss vs Placebo: Significant (dose-dependent); HbA1c: Not significant	25

(LFC = Liver Fat Content; Wt Loss = Weight Loss; FPG = Fasting Plasma Glucose; QW = Once Weekly; LS Mean = Least Squares Mean)

VI. Safety and Tolerability Profile

A. Overview

Across the Phase 2 clinical trials conducted, Efinopegdutide administration was generally associated with a higher frequency of treatment-emergent adverse events (TEAEs) compared to placebo and, in some cases, active comparators like Semaglutide 1mg and Liraglutide 3mg.[15]

B. Common Adverse Events

The safety profile of Efinopegdutide is dominated by gastrointestinal (GI) side effects, a characteristic shared with the GLP-1 receptor agonist class, but potentially amplified by the dual GLP-1/glucagon mechanism or the specific properties of the molecule.

• Obesity and T2DM Studies: In the Phase 2 studies involving participants with obesity or T2DM, the incidence of TEAEs, particularly nausea and vomiting, was reported to be higher in all Efinopegdutide dose groups compared to both placebo and the Liraglutide 3mg group.[23]
• NAFLD Study (NCT04944992): In the Phase 2a study comparing Efinopegdutide 10mg QW to Semaglutide 1mg QW in NAFLD patients, GI adverse events (most commonly reported as nausea or diarrhea) occurred in 56.9% of participants receiving Efinopegdutide versus 52.1% receiving Semaglutide.[24] The overall incidence of drug-related adverse events was also slightly higher in the Efinopegdutide arm (63.9%) compared to the Semaglutide arm (47.9%).[15]

This consistent pattern suggests that GI tolerability represents the primary safety challenge for Efinopegdutide. While common for incretin-based therapies, the higher reported rates compared to comparators in some studies might necessitate careful patient management, particularly during dose initiation and escalation.[15] This tolerability profile may have contributed to the decision to discontinue development for the broader obesity and T2DM indications.

C. Serious Adverse Events (SAEs) and Discontinuations

Despite the higher incidence of common GI side effects, the rate of serious adverse events and study discontinuations due to adverse events appeared relatively low in the NAFLD study, suggesting a manageable profile for many patients in the context of NASH treatment.

• NAFLD Study (NCT04944992): In this 24-week trial, serious adverse events were infrequent, reported in only one participant in each treatment arm (Efinopegdutide and Semaglutide). Importantly, no drug-related SAEs were observed in either group. Discontinuation of treatment due to drug-related adverse events occurred in 3 participants (4.2%) receiving Efinopegdutide, compared to zero participants receiving Semaglutide.[24] This manageable safety profile in the target NAFLD/NASH population likely supported the decision to advance Efinopegdutide into Phase 2b development.[4]
• Obesity Study (NCT03486392): Specific rates of SAEs or discontinuations for each dose group versus comparators are not detailed in the available abstracts, although the overall TEAE incidence was higher with Efinopegdutide.[23]
• Phase 1 T2DM Study Termination (NCT02862431): This early-phase study was terminated.[44] While the specific reasons are not provided in the snippets, termination of a Phase 1 trial can sometimes relate to unexpected safety or tolerability findings, or a clear lack of desired pharmacologic effect observed early on. Without further details, the precise implications of this termination for the overall safety assessment remain unclear, though subsequent Phase 2 trials proceeded and reported manageable safety in other populations.[15]

D. Cardiac Safety

A dedicated Phase 1 thorough QT (TQT) study (NCT03606057) was conducted, using moxifloxacin as a positive control, to rigorously evaluate Efinopegdutide's potential impact on cardiac repolarization (QTc interval).[32] This is a standard regulatory requirement for assessing arrhythmia risk. The specific results of this TQT study are not detailed in the provided research snippets. However, no major cardiac safety concerns were highlighted in the summaries of the Phase 2 trials discussed.

E. Management

To improve tolerability, particularly the common GI side effects, clinical trials typically employ a dose-titration strategy. For instance, in the Phase 2a NAFLD study, both Efinopegdutide and Semaglutide were titrated up to their target doses over an 8-week period.[15] This gradual increase in dosage allows the body to adapt and can help mitigate the intensity of initial side effects.

Table 4: Summary of Safety and Tolerability Findings (Phase 2 Studies)

Study (Identifier/Ref)	Indication	Efinopegdutide Dose(s) (QW)	Comparator(s) (QW)	Duration	Overall Drug-Related AE Incidence (%)	Most Common AEs (% incidence if available)	SAEs (%)	Discontinuations due to Drug-Related AEs (%)	Source Snippet(s)
NCT04944992	NAFLD	10mg	Semaglutide 1mg	24 Weeks	Efino: 63.9% Sema: 47.9%	GI (Nausea, Diarrhea): Efino: 56.9%, Sema: 52.1%	Efino: 1 pt (non-drug-related) Sema: 1 pt (non-drug-related)	Efino: 4.2% (3 pts) Sema: 0%	15
NCT03486392	Obesity (non-diabetic)	5mg, 7.4mg, 10mg	Placebo, Liraglutide 3mg	26 Weeks	Higher incidence vs Placebo & Liraglutide (overall TEAEs)	GI (Nausea, Vomiting): Higher incidence vs Placebo & Liraglutide	Not specified	Not specified	23
Ref: 25	T2DM with Obesity	5mg, 7.4mg, 10mg	Placebo	12 Weeks	Higher incidence vs Placebo (overall TEAEs)	GI (Nausea, Vomiting): Higher incidence vs Placebo	Not specified	Not specified	25

(AE = Adverse Event; GI = Gastrointestinal; SAE = Serious Adverse Event; QW = Once Weekly; pts = participants; Efino = Efinopegdutide; Sema = Semaglutide)

VII. Regulatory Status and Future Outlook

A. Current Regulatory Status

Efinopegdutide remains an investigational drug candidate. It has not received marketing approval from any regulatory agency, including the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA), for any indication.[4]

B. FDA Fast Track Designation

A significant regulatory milestone was achieved in June 2023 when the FDA granted Fast Track Designation to Efinopegdutide (MK-6024) for the treatment of NASH.[4] This designation is intended for drugs being developed for serious conditions with unmet medical needs. It aims to facilitate development and expedite the review process through benefits such as more frequent interactions with the FDA and potential eligibility for Accelerated Approval and Priority Review, provided relevant criteria are met.[4] The granting of this designation likely reflects the promising preliminary data, particularly the substantial liver fat reduction observed in Phase 2a, and the significant lack of approved therapies for NASH.

C. EMA Status

There is no mention in the provided materials of Efinopegdutide receiving specific expedited pathway designations from the EMA, such as PRIME (PRIority MEdicines). However, clinical trials involving Efinopegdutide are actively being conducted in European Union member states, registered under the EudraCT system and the newer EU Clinical Trial Regulation (CTR) framework.[15] For instance, trials are ongoing or recruiting in countries like France and Spain.[62] The EMA's role is to evaluate marketing authorisation applications submitted via the centralised procedure and provide recommendations to the European Commission, which grants the final marketing authorisation valid throughout the EU/EEA.[65]

D. Ongoing and Planned Clinical Development

Merck is actively advancing Efinopegdutide through mid-stage clinical trials focused on liver disease:

• Phase 2b NASH Trial (NCT05877547 / IRAS 1007627): This crucial multicenter study is evaluating the efficacy and safety of three doses of Efinopegdutide (4mg, 7mg, 10mg QW) compared to placebo over 52 weeks in approximately 300 adults with biopsy-confirmed precirrhotic NASH (fibrosis stages F2-F3).[4] The primary endpoints are expected to be histological improvements, such as NASH resolution without worsening of fibrosis, or improvement in liver fibrosis stage without worsening of NASH – endpoints typically required for NASH drug approval. The study design also includes an open-label arm with Semaglutide 2.4mg QW as an active comparator (in the UK protocol), providing valuable comparative data against a high-dose GLP-1RA standard.[5] This trial commenced around June 2023.[4]
• Phase 2 MASH Cirrhosis Trial (NCT06465186): This study is currently recruiting approximately 80 participants with MASH and compensated cirrhosis (stage F4 fibrosis).[3] It aims to assess the efficacy (effects on liver fat, inflammation, and fibrosis markers) and safety of Efinopegdutide versus placebo over 28 weeks in this advanced patient population with high unmet need.
• Phase 2 Alternate Dosing Trial (NCT06482112 / EU CT 2024-510923-20-00): This trial is actively recruiting participants with MASLD to compare the effects of administering Efinopegdutide once every two weeks (Q2W) versus the established once-weekly (Q1W) regimen.[18] The study will evaluate LFC reduction, safety, and tolerability over 28 weeks. This exploration suggests Merck is seeking to optimize the dosing schedule, potentially to improve the tolerability profile (e.g., reducing peak exposures associated with GI side effects) or enhance patient convenience and long-term adherence.[39]

E. Future Prospects

Efinopegdutide holds potential as a novel therapeutic agent for NASH/MASH, differentiated by its dual GLP-1R/GCGR agonist mechanism. Its future trajectory hinges significantly on the outcomes of the ongoing Phase 2b trial (NCT05877547).[4] Demonstrating clear histological benefit (NASH resolution and/or fibrosis improvement) with a manageable safety profile, particularly in comparison to high-dose Semaglutide, would provide strong rationale for advancing into larger Phase 3 pivotal trials and subsequent regulatory submissions. Positive results from the cirrhosis and alternate dosing studies would further delineate its potential clinical utility across different patient segments and optimize its application. Conversely, failure to meet the histological endpoints in the Phase 2b study would represent a major setback for the program.

VIII. Conclusion

Efinopegdutide (MK-6024) is an investigational fusion protein engineered as a potent dual agonist of the GLP-1 and glucagon receptors, designed for once-weekly subcutaneous administration. Its development history reflects a strategic pivot from initial exploration in obesity and T2DM by Janssen to a focused pursuit of NASH/MASH indications by Merck, driven by the hypothesis that its dual mechanism offers unique advantages for treating metabolic liver disease.

Clinical evidence, particularly from the Phase 2a NAFLD study (NCT04944992), supports this hypothesis, demonstrating a significantly greater reduction in liver fat content with Efinopegdutide compared to Semaglutide 1mg, even with non-significantly different weight loss. This finding suggests a direct, beneficial hepatic effect mediated by glucagon receptor agonism, complementing the weight-loss effects of GLP-1 agonism. However, the drug failed to improve glycemic control in patients with T2DM, highlighting the challenge of balancing the opposing metabolic effects of the two targeted hormones and justifying the discontinuation of development for diabetes.

The safety profile observed in Phase 2 trials is characterized primarily by gastrointestinal adverse events (nausea, vomiting, diarrhea), occurring at a higher frequency than placebo and sometimes active comparators. While these effects appear manageable in the NAFLD/NASH context with dose titration, contributing to low discontinuation rates in the Phase 2a study, tolerability remains a key consideration.

Currently progressing through Phase 2b development for precirrhotic NASH (NCT05877547), with studies also ongoing in MASH with cirrhosis (NCT06465186) and evaluating alternate dosing regimens (NCT06482112), Efinopegdutide's future prospects are critically dependent on demonstrating histological efficacy in the ongoing NASH trial. Success in achieving NASH resolution or fibrosis improvement, coupled with a continued manageable safety profile, would position Efinopegdutide as a potentially valuable therapeutic option in an area of high unmet medical need, further validating the dual GLP-1/glucagon agonist approach for treating metabolic liver disease. The FDA's granting of Fast Track Designation underscores its potential significance.

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