Mibenratide (JNJ-54452840, COR-1): An Investigational Peptide for Heart Failure

1. Introduction to Mibenratide

Mibenratide, also identified by its developmental codes JNJ-54452840 and COR-1, is an investigational synthetic cyclic peptide that was evaluated for the treatment of heart failure.[1] Its therapeutic approach was particularly focused on a subset of heart failure patients characterized by the presence of autoantibodies against the beta1-adrenergic receptor (anti-β1-AR).[2] This targeted strategy aimed to address a specific pathophysiological mechanism believed to contribute to the progression of heart failure in these individuals.

The development of Mibenratide originated with Corimmun GmbH, a German biotechnology company, where it was known as COR-1.[3] Recognizing its potential, Janssen-Cilag GmbH, a subsidiary of Johnson & Johnson, acquired Corimmun in 2012, thereby taking over the full development and global commercialization responsibilities for the compound, subsequently known as JNJ-54452840 and later Mibenratide.[3] Such acquisitions in the pharmaceutical industry are typically driven by promising preclinical or early clinical data and the perceived market potential of a novel therapeutic agent. Corimmun's focus on COR-1 as its lead compound suggests it was the central asset of the company.[3] Janssen's decision to acquire it indicates a perceived value and potential for Mibenratide to address an unmet medical need in heart failure.

Mibenratide progressed to Phase 2 clinical trials.[2] However, its development was ultimately discontinued.[2] The clinical trial NCT01798745, a Phase 2 study designed to assess its pharmacokinetics and pharmacodynamics in heart failure patients with anti-β1-AR autoantibodies, was withdrawn prior to completion.[4] This discontinuation, after reaching a significant stage of clinical investigation, points to the emergence of challenges—whether related to efficacy, safety, pharmacokinetics, or strategic re-evaluation—that outweighed its initial promise.

Mibenratide represents a notable attempt to develop a novel therapeutic for a specific subpopulation of heart failure patients by targeting underlying autoimmune mechanisms. Its development pathway, from a smaller biotech innovation to acquisition by a major pharmaceutical entity and subsequent discontinuation, underscores the inherent risks and high attrition rates in pharmaceutical research and development, even for compounds with innovative mechanisms of action and significant initial backing. The journey of Mibenratide offers valuable insights into the complexities of translating novel scientific concepts into viable therapies.

2. Chemical and Physical Properties

Mibenratide is classified as a synthetic cyclic peptide.[1] While some databases like DrugBank categorize it broadly as a "Small Molecule" [9] and PubChem as a "Protein drug" [4], its specific structure as an 18-amino acid cyclic peptide places it distinctly in the peptide therapeutic class. This classification is significant, as peptides often exhibit different pharmacokinetic, pharmacodynamic, and immunogenic profiles compared to traditional organic small molecules.

The chemical and physical properties of Mibenratide are summarized in Table 1.

Table 1: Chemical and Physical Properties of Mibenratide

Property	Details	Reference(s)
Drug Type	Synthetic cyclic peptide	1
Molecular Formula	C87​H129​N27​O30​S2​	1
Molecular Weight	Approx. 2097.25 - 2097.3 g/mol	1
Amino Acid Sequence	Cyclo(Ala-Arg-Arg-Cys-Tyr-Asn-Asp-Pro-Lys-Cys-Ser-Asp-Phe-Val-Gln-Ala-Asp-Glu)	1
Shortened Sequence	Cyclo(ARRCYNDPKCSDFVQADE)	1
Disulfide Bridge	Between Cys4 and Cys10	1
IUPAC Name	cyclo[L-alanyl-L-arginyl-L-arginyl-L-cysteinyl-L-tyrosyl-L-asparagyl-L-alpha-aspartyl-L-prolyl-L-lysyl-L-cysteinyl-L-seryl-L-alpha-aspartyl-L-phenylalanyl-L-valyl-L-glutaminyl-L-alanyl-L-alpha-aspartyl-L-alpha-glutamyl] (4->10)-disulfide	4
CAS Number	1239011-83-6	1
DrugBank ID	DB15195	4
Synonyms	JNJ-54452840, COR-1, mibenratida, mibenratidum	1
Appearance	White to off-white solid	1
Solubility	DMSO: 100 mg/mL (hygroscopic); Water: 0.357 mg/mL	9

Mibenratide is a well-characterized peptide. Its cyclic structure, maintained by a disulfide bond between the cysteine residues at positions 4 and 10, is crucial for its three-dimensional conformation and, consequently, its biological activity.[1] Such structural constraints are often designed into peptide therapeutics to enhance stability against proteolytic degradation, improve receptor binding affinity and specificity by mimicking protein loops or native conformations, and favorably influence pharmacokinetic properties. For a peptide intended to interact with specific autoantibodies or cell surface receptors, a stable and well-defined structure is paramount for consistent and predictable biological effects.

The relatively large size of Mibenratide (molecular weight approximately 2.1 kDa) and its peptidic nature distinguish it from typical "small molecule" drugs. These characteristics inherently carry a higher potential for immunogenicity, a factor that indeed manifested during its clinical development and likely contributed to the challenges encountered.[5]

3. Mechanism of Action

Mibenratide's therapeutic strategy was centered on modulating the autoimmune response believed to contribute to the pathology of certain forms of heart failure.

Target Receptor and Pathogenic Autoantibodies:

The primary molecular target associated with Mibenratide is the β1-adrenergic receptor (β1-AR).2 More specifically, the drug was developed for individuals with heart failure who exhibit circulating autoantibodies directed against this receptor (anti-β1-AR AAb).2 These autoantibodies are not merely biomarkers but are considered pathogenic effectors in a subset of patients with heart conditions such as dilated cardiomyopathy (DCM). It is understood that these autoantibodies often possess agonist-like properties, meaning they can bind to and chronically stimulate the β1-AR in a manner similar to natural catecholamines like adrenaline and noradrenaline.5 This aberrant, persistent stimulation of cardiac β1-ARs can lead to a cascade of detrimental downstream effects, including increased intracellular calcium, myocyte apoptosis, receptor uncoupling, and ultimately, progressive myocardial damage and dysfunction, contributing to the development and worsening of heart failure.11 Approximately 25-40% of patients with DCM have been reported to have such activating autoantibodies against the human β1-AR.11

Proposed Mechanism of Mibenratide:

Mibenratide (JNJ-54452840/COR-1) was designed as an "epitope-mimicking cyclopeptide".13 The core proposed mechanism of action for Mibenratide is the neutralization or interference with these pathogenic anti-β1-AR autoantibodies.3 It is described as a peptide that may function through "binding interference and decreased production of anti-β1-adrenergic receptor (anti-β1-AR) antibodies" 2 or by "decreasing autoimmune, beta 1 receptor-simulating antibody effects".3 This suggests that Mibenratide might act as a "scavenger" or decoy, binding to the circulating autoantibodies and preventing them from interacting with and stimulating the β1-ARs on cardiomyocytes.

Some sources also broadly classify Mibenratide as a β1-adrenergic receptor antagonist.[1] This classification could imply a direct blockade of the receptor itself, in addition to or as a consequence of autoantibody neutralization. If Mibenratide directly binds to the β1-AR with antagonistic properties, its effects might extend beyond just patients with high autoantibody titers and could potentially interact with standard beta-blocker therapies. However, the primary focus of its development and the design of clinical trials like NCT01798745 (which specifically enrolled patients with anti-β1-AR autoantibodies) strongly suggest that the autoantibody neutralization pathway was the principal intended mechanism.[4]

Therapeutic Rationale:

The therapeutic rationale was that by neutralizing these pathogenic autoantibodies or interfering with their binding to the β1-AR, Mibenratide would reduce the chronic, aberrant stimulation of cardiac β1-ARs. This, in turn, was hypothesized to alleviate downstream detrimental signaling, protect cardiomyocytes from ongoing damage, and ultimately lead to an improvement in heart function and a reduction in heart failure symptoms.3 This immunomodulatory approach represented a departure from conventional heart failure therapies that primarily target hemodynamic and neurohormonal pathways.

The success of such a therapeutic strategy hinges on several factors, including the specificity of Mibenratide for the truly pathogenic autoantibodies versus other non-harmful immunoglobulins. If the peptide were to broadly suppress immune responses or bind non-pathogenic antibodies, it could lead to undesirable immunomodulatory side effects. Furthermore, the development of anti-drug antibodies (ADAs) against Mibenratide itself, as was observed in early clinical studies [5], could potentially interfere with its ability to neutralize the target autoantibodies or lead to the formation of immune complexes with distinct pathological consequences.

Targeting autoantibodies in heart failure remains a complex but potentially rewarding frontier. If a therapy like Mibenratide were to be successful, it could pave the way for more personalized medicine approaches in cardiology, where patient selection for specific treatments is guided by their autoantibody profiles. The challenges encountered during Mibenratide's development provide important lessons for this evolving field.

4. Pharmacokinetics (PK)

The pharmacokinetic profile of Mibenratide in humans was primarily investigated in the Phase 1 clinical trial NCT01809353. This study involved the administration of single intravenous (IV) doses (20 mg, 80 mg, 240 mg, and placebo) to 32 healthy male participants, equally divided between Japanese and Caucasian ethnic groups.[2]

Table 2: Summary of Mibenratide Pharmacokinetic Parameters in Healthy Volunteers (NCT01809353)

(Specific values for Cmax, AUCinf, CL, Vss are not detailed in provided snippets beyond trends and comparisons; T½ and Tmax ranges are provided)

PK Parameter	Dose Level (IV)	Observation	Population	Reference(s)
Tmax (Time to Cmax)	20, 80, 240 mg	1 to 5 minutes	Japanese & Caucasian	2
Elimination	20, 80, 240 mg	Rapid	Japanese & Caucasian	2
T½ (Terminal Half-life)	20, 80, 240 mg	5.9 to 26.1 minutes (dose-dependent)	Japanese & Caucasian	2
Cmax & AUCinf	20, 80, 240 mg	Increased linearly with dose	Japanese & Caucasian	2
Dose Proportionality	20 mg vs 240 mg	Criteria not met	Japanese & Caucasian	2
CL (Total Systemic Clearance)	20, 80, 240 mg	Similar between groups	Japanese & Caucasian	2
Vss (Volume of Distribution at Steady State)	20, 80, 240 mg	Similar between groups	Japanese & Caucasian	2

Absorption and Distribution:

Mibenratide was administered intravenously in clinical studies.5 Following IV infusion, peak plasma concentrations (Cmax) were achieved very rapidly, with a median Tmax ranging from 1 to 5 minutes.5 This indicates immediate systemic availability, as expected with IV administration. The volume of distribution at steady state (Vss) was reported to be similar for both Japanese and Caucasian participants, although specific values were not provided in the available information.5

Metabolism:

The specifics of Mibenratide's metabolism are not detailed in the provided documentation. However, peptides, in general, are susceptible to enzymatic degradation by proteases and peptidases in the blood and tissues. The observed rapid elimination of Mibenratide is consistent with such metabolic pathways.

Elimination:

Mibenratide demonstrated rapid elimination from the systemic circulation in both Japanese and Caucasian healthy volunteers.5 The mean terminal half-life (T½) was very short, ranging from 5.9 to 26.1 minutes, and appeared to be dose-dependent.5 The mean total systemic clearance (CL) was reported as similar between the ethnic groups studied.5

Dose Proportionality:

While the mean Cmax and area under the concentration-time curve from time zero to infinity (AUCinf) values were reported to increase linearly with dose, formal dose proportionality criteria were not met across the full dose range studied (20 mg to 240 mg) for either cohort.5 This lack of strict dose proportionality suggests the involvement of saturable processes in Mibenratide's pharmacokinetics, such as saturable binding, distribution, or clearance mechanisms, particularly at higher dose levels. Such non-linearities can complicate dose selection and the prediction of drug exposure in different patient populations or at varying doses.

Ethnic Differences:

The pharmacokinetic profile of Mibenratide was generally found to be similar between healthy male Japanese and Caucasian participants.5

The very short half-life of Mibenratide presents a significant practical challenge for its therapeutic application, especially in the context of a chronic condition like heart failure. Such rapid elimination would typically necessitate frequent intravenous administrations or the development of a continuous infusion formulation to maintain potentially therapeutic drug concentrations. This high dosing frequency could increase treatment burden, reduce patient compliance, and elevate healthcare costs. While the Phase 2 pilot study in DCM patients utilized dosing every 4 weeks [13], the immediate pharmacokinetic data suggest that the drug would not be present at significant concentrations for the majority of this dosing interval. This discrepancy raises questions about whether the intended therapeutic effect relies on sustained target engagement despite rapid clearance (e.g., through very high affinity binding, irreversible effects, or long-lasting downstream biological modifications) or if intermittent exposure was deemed sufficient, a less common paradigm for such targets. These pharmacokinetic characteristics, particularly the short half-life and non-dose-proportional behavior, may have been contributing factors to the eventual discontinuation of Mibenratide's development, alongside efficacy and safety considerations.

5. Pharmacodynamics (PD)

The pharmacodynamic effects of Mibenratide were intended to be linked to its mechanism of action, primarily the neutralization or modulation of pathogenic anti-β1-AR autoantibodies in heart failure patients.

Target Engagement and Autoantibody Modulation:

The clinical trial NCT01798745 was specifically designed to evaluate "A Study to Assess the Pharmacokinetics and Pharmacodynamics of JNJ-54452840 in Participants With Heart Failure and Anti-beta1-adrenergic Receptor Autoantibodies".4 This study would have been crucial for providing direct evidence of Mibenratide's ability to engage its target and alter the levels or activity of these autoantibodies in the intended patient population. However, NCT01798745 was withdrawn prior to completion, and as such, specific pharmacodynamic results regarding the direct effects on anti-β1-AR autoantibody levels in heart failure patients are not available in the provided documentation.2

The Phase 1 study in healthy volunteers (NCT01809353) did include monitoring of anti-β1-AR antibodies. This study reported a baseline prevalence of such antibodies (or cross-reactive antibodies) in 9.4% of participants. More significantly, it was observed that de novo antibodies, likely anti-drug antibodies (ADAs) against JNJ-54452840 itself rather than a modulation of pre-existing anti-β1-AR autoantibodies, developed in 15.6% of Caucasian participants following single doses. No such de novo antibody formation was reported in Japanese participants in that study.[2] This immunogenicity is a critical pharmacodynamic consideration, as ADAs can impact a drug's efficacy, safety, and pharmacokinetic profile.

Effects on Cardiac Function (Phase 2 Pilot Study in DCM patients):

Limited pharmacodynamic and efficacy data on cardiac function come from a Phase 2 pilot study involving 36 patients with Dilated Cardiomyopathy (DCM) and circulating anti-β1-AR autoantibodies. Patients received Mibenratide (JNJ-54452840/COR-1) at doses of 20 mg, 80 mg, or 160 mg, or placebo, administered intravenously every 4 weeks for 6 doses, in addition to standard guideline-recommended heart failure therapy.13

Table 3: Summary of Pharmacodynamic and Efficacy Outcomes from Mibenratide Clinical Studies

Outcome Measure	Study / Population	Dose Group	Result	Reference(s)
Anti-Drug Antibody (ADA) Formation	NCT01809353 / Healthy Volunteers	Single IV doses (20, 80, 240 mg)	15.6% in Caucasians (de novo); 0% in Japanese (de novo); 9.4% baseline prevalence (overall)	2
Left Ventricular Ejection Fraction (LVEF) - Centrally Assessed	Phase 2 Pilot / DCM Patients	80 mg JNJ-54452840	+5.4% change from baseline	13
		Placebo	-1.6% change from baseline	13
LVEF - Locally Assessed	Phase 2 Pilot / DCM Patients	All groups	Similar to primary results; interpreted by source as "suggesting lack of treatment effect from baseline to month 9"	13
NT-proBNP	Phase 2 Pilot / DCM Patients	JNJ-54452840 vs. Placebo	No significant improvement in JNJ-54452840 groups	13
6-Minute Walk Test	Phase 2 Pilot / DCM Patients	JNJ-54452840 & Placebo	Numerical increase from baseline in both groups	13

Key findings from this pilot study included [13]:

• Left Ventricular Ejection Fraction (LVEF): The primary efficacy endpoint, change in centrally-assessed LVEF, showed an increase of +5.4% in the 80 mg JNJ-54452840 group compared to a decrease of -1.6% in the placebo group. However, the interpretation of locally-assessed LVEF values, though reportedly similar to the primary results, was stated as "suggesting lack of treatment effect from baseline to month 9." This apparent discrepancy in interpretation or the nuances of the data could have weakened the confidence in the LVEF improvement. Centralized readings in clinical trials aim to standardize assessments; if local site readings did not robustly corroborate the central findings, or if the magnitude of change from baseline was not considered clinically meaningful despite a difference from placebo, it would diminish the perceived efficacy.
• NT-proBNP: Levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP), a standard prognostic biomarker in heart failure, varied considerably among patients and did not show significant improvement in the Mibenratide-treated groups compared to placebo. The absence of a favorable impact on such a key biomarker, despite potential LVEF changes, is a notable limitation, as clinically meaningful improvements in heart failure are often expected to be reflected in biomarker profiles.
• 6-Minute Walk Test: Both Mibenratide and placebo groups demonstrated a numerical increase in the distance walked in 6 minutes from baseline to month 6, suggesting no clear drug-specific benefit on this measure of functional capacity.

The Phase 2 pilot study was originally planned to recruit 160 patients but was amended to a pilot study involving only 36 patients for "strategic reasons".[13] Consequently, the study authors concluded that "no definitive statements on the efficacy of JNJ-54452840 in DCM patients with circulating anti-β1-Abs can be made, although centrally-assessed LVEF appeared to improve in the 80 mg group".[13]

The limited and somewhat inconsistent pharmacodynamic and efficacy signals from this small pilot study, particularly the lack of robust improvement in biomarkers like NT-proBNP and functional capacity, coupled with the pharmacokinetic challenges and emerging safety concerns, likely contributed to the decision to discontinue the development of Mibenratide. Without clear evidence of consistent target engagement (i.e., reduction of pathogenic autoantibody levels or activity) and corresponding, unequivocal improvements in key cardiac parameters, proceeding to larger, more definitive, and costly Phase 3 trials would have represented a substantial risk.

6. Clinical Development Program

The clinical development of Mibenratide (JNJ-54452840/COR-1) involved several key studies, primarily in early phases, before its discontinuation.

Table 4: Overview of Key Clinical Trials for Mibenratide

Trial ID	Phase	Official Title / Brief Description	Sponsor	Status	Population	Key Objectives	Outcome/Reason for Status	Reference(s)
NCT01798745	2 (2A)	A Study to Assess the Pharmacokinetics and Pharmacodynamics of JNJ-54452840 in Participants With Heart Failure and Anti-beta1-adrenergic Receptor Autoantibodies	Janssen Research & Development, LLC	Withdrawn	Patients with heart failure (reduced systolic function) and elevated anti-β1-AR autoantibodies	Assess PK and PD	Withdrawn prior to completion; "strategic reasons" cited for amending a related Phase 2 study to a pilot	2
NCT01809353	1	A Phase 1 Randomized, Double-Blind, Placebo-Controlled Crossover Study to Evaluate the Pharmacokinetics and Safety of JNJ-54452840 Following Single Intravenous Doses to Healthy Japanese and Caucasian Subjects	Janssen Research & Development, LLC	Completed	Healthy male Japanese and Caucasian volunteers	Evaluate PK and safety of single IV doses	PK characterized (rapid elimination, dose-dependent T½); safety signals including immunogenicity and thromboembolic events observed	2
NCT01902550	1	A Randomized, Double-Blind, 2-Period Crossover Study to Evaluate the Effect of Single Dose JNJ-54452840 on Pharmacodynamics of Metoprolol Tartrate Immediate-Release in Healthy Subjects	Janssen Research & Development, LLC	Withdrawn	Healthy volunteers	Assess drug-drug interaction with metoprolol	Withdrawn prior to completion	2
Phase 2 Pilot Study (DCM)	2	Randomized, double-blind, placebo-controlled pilot study in DCM patients with anti-β1-Abs	Janssen Research & Development, LLC (post-acquisition of Corimmun)	Completed (as pilot)	36 Caucasian DCM patients with anti-β1-Abs	Effects on cardiac function (LVEF, NT-proBNP, 6MWT), safety	LVEF increase in 80mg group (centrally assessed), no NT-proBNP improvement. No new compound-related safety signals in this specific study. Amended from larger study for "strategic reasons".	13

Efficacy Findings Detailed Discussion:

The available efficacy data for Mibenratide are sparse, primarily derived from the aforementioned Phase 2 pilot study in 36 DCM patients.13

• LVEF: The most promising finding was the +5.4% increase in centrally-assessed LVEF in the 80 mg Mibenratide group, compared to a -1.6% decrease in the placebo group. However, the sample size per arm was very small (likely around 9 patients), limiting the statistical power and robustness of this observation. Furthermore, the accompanying note that locally-assessed LVEF values, while "similar to primary results," suggested a "lack of treatment effect from baseline to month 9" introduces ambiguity and tempers enthusiasm for the LVEF finding. Such discrepancies between central and local reads, or nuanced interpretations of overall change, can significantly impact the perception of efficacy.
• NT-proBNP: The failure to demonstrate a significant improvement in NT-proBNP levels, a well-established biomarker for heart failure severity and prognosis, was a notable negative outcome.
• 6-Minute Walk Test: Numerical increases in exercise capacity were seen in both the Mibenratide and placebo groups, indicating no clear drug-attributable benefit.

Given the pilot nature of this amended study, the authors rightly concluded that "no definitive statements on the efficacy... can be made".[13] The limited and somewhat inconsistent efficacy signals, especially the lack of corroborating biomarker or functional improvements, would have made it difficult to justify progression to larger, more resource-intensive Phase 3 trials.

Safety and Tolerability Profile Detailed Discussion:

The safety profile of Mibenratide raised considerable concerns, particularly from the Phase 1 study in healthy volunteers (NCT01809353).2

Table 5: Summary of Key Safety Findings for Mibenratide

Study	Population	Key Safety Finding	Details	Reference(s)
NCT01809353 (Phase 1)	Healthy Male Volunteers	Immunogenicity (Anti-Drug Antibodies)	- 15.6% of Caucasian participants developed de novo ADAs. <br> - 0% of Japanese participants developed de novo ADAs. <br> - 9.4% overall baseline prevalence of (potentially cross-reactive) antibodies.	2
		Serious Thromboembolic Events	- One Caucasian participant: Pulmonary Embolism. <br> - One Japanese participant: Ischemic Stroke. <br> - Relationship to ADAs or drug: "not known".	2
Phase 2 Pilot Study (DCM)	DCM Patients	Common Adverse Events (JNJ-54452840 arms)	- Cardiac failure (n=4) <br> - Nasopharyngitis (n=4) <br> - Cough (n=3) <br> - Sinusitis (n=3) <br> - Increased heart rate (n=3)	13
		Overall Tolerability in Study	"No compound-related safety or tolerability signals were observed" within this specific pilot study.	13

In the Phase 1 study (NCT01809353), two major safety issues emerged:

1. Immunogenicity: The development of anti-JNJ-54452840 antibodies (ADAs) was observed in a notable portion (15.6%) of Caucasian participants after single doses. This is a concern for peptide and protein therapeutics as ADAs can neutralize the drug, alter its pharmacokinetics, or, in some cases, lead to hypersensitivity reactions or other adverse events. The observed ethnic disparity, with no ADAs detected in Japanese participants, is a significant pharmacogenomic finding, suggesting that genetic factors, possibly related to HLA types, may influence the immune response to Mibenratide. Such differences would complicate global drug development and require tailored risk assessments.
2. Serious Thromboembolic Events: The occurrence of two serious thromboembolic events—a pulmonary embolism in one Caucasian participant and an ischemic stroke in one Japanese participant—in a relatively small study of 32 healthy volunteers is a critical safety signal.[5] While the study report stated that the relationship between these events and ADA formation or the drug itself was "not known," the appearance of such severe events in healthy individuals, who are typically at a lower baseline risk for thromboembolism than heart failure patients, would be a major cause for concern in any drug development program. These events alone could significantly shift the risk-benefit calculus against further development.

In the subsequent Phase 2 pilot study conducted in DCM patients, the reported common adverse events included cardiac failure, nasopharyngitis, cough, sinusitis, and increased heart rate.[13] The investigators of this particular pilot study concluded that "No compound-related safety or tolerability signals were observed." This statement might reflect that the observed AEs were considered consistent with the underlying disease or background rates in this patient population, or that no new, unexpected safety issues directly attributable to Mibenratide emerged within that specific, small cohort. However, the serious safety signals from the earlier Phase 1 study in healthy volunteers would undoubtedly have remained a primary consideration in the overall assessment of Mibenratide's development viability.

The combination of these safety concerns—immunogenicity with ethnic variation and, most critically, the serious thromboembolic events—when weighed against the modest and somewhat uncertain efficacy data, likely formed a compelling case for the discontinuation of Mibenratide's clinical development.

7. Regulatory Status and Development History

Mibenratide, initially known as COR-1, was conceived and first developed by Corimmun GmbH, a German biotechnology company that originated as a spin-off from the Universities of Würzburg and Tübingen.[3] Corimmun focused on COR-1 as its lead compound for heart failure.[3]

In a significant step for its development, Corimmun GmbH was acquired by Janssen-Cilag GmbH, a pharmaceutical company of Johnson & Johnson, in June 2012.[3] This acquisition involved an upfront payment and a contingent future clinical milestone payment. Following the acquisition, Janssen and its affiliates assumed full responsibility for the continued development and potential global commercialization of COR-1, which was then assigned the development code JNJ-54452840 and subsequently named Mibenratide.[2]

Mibenratide progressed to Phase 2 in its clinical development pathway.[2] Key clinical trials undertaken include:

• NCT01809353: A Phase 1 study evaluating pharmacokinetics and safety in healthy Japanese and Caucasian volunteers, which was completed.[2] This study yielded important PK data and also highlighted safety concerns regarding immunogenicity and thromboembolic events.[5]
• Phase 2 Pilot Study in Dilated Cardiomyopathy: This study in DCM patients with anti-β1-AR autoantibodies provided limited efficacy signals.[13] It was notably amended from an initially planned larger Phase 2 trial to a smaller pilot study for "strategic reasons".[13]
• NCT01798745: A Phase 2a study intended to further assess pharmacokinetics and pharmacodynamics in heart failure patients with anti-β1-AR autoantibodies. This trial was ultimately withdrawn prior to completion.[2]
• NCT01902550: A Phase 1 drug-drug interaction study with metoprolol, which was also withdrawn before completion.[2]

The current regulatory and developmental status of Mibenratide is discontinued.[2] The explicit reasons for the discontinuation of the overall program and the withdrawal of specific trials like NCT01798745 and NCT01902550 are not detailed comprehensively in the provided documents, beyond the mention of "strategic reasons" for the amendment of the Phase 2 study to a pilot.[13] In the pharmaceutical industry, such "strategic reasons" can encompass a range of factors, including emerging unfavorable data related to efficacy or safety, a shifting competitive landscape, changes in corporate R&D priorities, or unfavorable projections regarding the cost of further development versus the potential return on investment. Given the observed pharmacokinetic challenges (very short half-life), the limited and somewhat inconsistent efficacy signals from the pilot study, and particularly the significant safety signals (immunogenicity and serious thromboembolic events in healthy volunteers), it is highly probable that these scientific and clinical findings collectively contributed to a risk-benefit assessment that did not support continued development.

The development trajectory of Mibenratide—from a promising innovation at a smaller biotech, leading to acquisition by a major pharmaceutical company, followed by eventual discontinuation during Phase 2—is a narrative frequently encountered in the challenging landscape of drug development. It highlights the rigorous scrutiny and critical decision points that investigational drugs face, where a combination of scientific, clinical, safety, and strategic considerations ultimately determines their path forward.

8. Discussion and Future Perspectives

Mibenratide (JNJ-54452840, COR-1) represented an innovative therapeutic concept for heart failure, distinguished by its novel mechanism of action targeting anti-β1-adrenergic receptor (anti-β1-AR) autoantibodies.[3] This approach held promise for a subset of heart failure patients where autoimmune processes are believed to play a significant pathogenic role.[11] However, despite this innovative rationale, the clinical development program for Mibenratide was discontinued, likely due to a confluence of factors related to its efficacy, pharmacokinetic profile, and safety.

Critical Analysis of Mibenratide's Profile:

The therapeutic potential of Mibenratide was suggested by its unique mechanism. The observation of a +5.4% increase in centrally-assessed Left Ventricular Ejection Fraction (LVEF) in the 80 mg arm of a small Phase 2 pilot study in Dilated Cardiomyopathy (DCM) patients provided an initial, albeit limited, efficacy signal.13 However, this finding was not robustly supported by improvements in other key cardiac biomarkers, such as NT-proBNP, or functional measures like the 6-minute walk test. Furthermore, discrepancies or cautious interpretations regarding locally-assessed LVEF data added to the uncertainty surrounding its clinical benefit.13

The pharmacokinetic profile of Mibenratide presented considerable challenges. Its very short terminal half-life of 5.9 to 26.1 minutes in healthy volunteers would necessitate frequent intravenous administration to maintain therapeutic concentrations, a significant burden for a chronic condition like heart failure.[5] Moreover, the lack of clear pharmacodynamic data demonstrating effective and sustained neutralization of anti-β1-AR autoantibody levels in patients, partly due to the withdrawal of the key PD study (NCT01798745), left a critical gap in understanding its target engagement and dose-response relationship in the intended population.[2]

Safety concerns emerged as a major impediment. The development of anti-drug antibodies (immunogenicity), particularly with an observed ethnic disparity (higher in Caucasians than Japanese participants in a Phase 1 study), raised concerns about potential impacts on efficacy and safety with repeated dosing.[5] Most critically, the occurrence of serious thromboembolic events (pulmonary embolism and ischemic stroke) in two healthy volunteers during the Phase 1 study constituted a significant safety red flag.[5] Such events, even if a definitive causal link to the drug was not established, would heavily influence the risk-benefit assessment, especially for a condition where alternative treatments exist. The withdrawal of the drug-drug interaction study with metoprolol (NCT01902550) before its completion might also indicate that the overall development program was already facing substantial hurdles, or that preliminary interaction signals were unfavorable, further complicating its potential use in heart failure patients who are commonly on beta-blocker therapy.[2]

Unmet Needs and Challenges in Targeting Autoimmunity in Heart Disease:

Heart failure remains a leading cause of morbidity and mortality worldwide, and there is a continuous search for novel therapeutic targets and strategies, especially for patient populations that do not respond optimally to existing treatments.3 The concept of an autoimmune contribution to some forms of heart disease, such as DCM associated with anti-β1-AR autoantibodies, is an area of active research.11 However, translating this understanding into effective and safe therapies is fraught with challenges. These include accurately identifying the specific autoantibodies that are truly pathogenic versus those that are mere epiphenomena, developing therapies that can selectively neutralize these pathogenic autoantibodies without causing broad immunosuppression or eliciting significant immunogenicity themselves, and addressing the inherent heterogeneity of heart failure populations.

Lessons Learned and Future Directions:

The development of Mibenratide offers several important lessons. It underscores the importance of early and thorough pharmacokinetic and pharmacodynamic characterization for peptide-based therapeutics. The emergence of ethnic differences in immunogenicity highlights the need for careful consideration of population diversity in early clinical development. Most importantly, it reinforces the paramount importance of a favorable safety profile; significant safety signals, especially in healthy volunteers, can derail even mechanistically innovative compounds.

Future efforts to target autoimmune components in heart failure may benefit from these lessons. Strategies could include:

• Improved patient stratification techniques to identify individuals most likely to benefit from autoantibody-directed therapies, perhaps using more refined autoantibody profiling.
• The development of next-generation therapeutic modalities with reduced immunogenicity, such as modified peptides, small molecule modulators of autoantibody production or function, or highly specific antibody-based therapies.
• Further fundamental research to delineate the precise roles and mechanisms of various cardiac autoantibodies in the initiation and progression of heart failure.

While Mibenratide did not achieve its therapeutic goals, the scientific rationale of addressing autoimmune contributions to heart failure remains a valid area of investigation. The knowledge gained from its development journey can inform and guide future research aimed at delivering novel treatments for this complex and devastating disease.

9. Conclusion

Mibenratide (JNJ-54452840, COR-1) was an investigational synthetic cyclic peptide developed as a novel therapeutic agent for heart failure, specifically targeting patients with circulating anti-β1-adrenergic receptor (anti-β1-AR) autoantibodies. Its proposed mechanism of action, involving the neutralization or interference with these pathogenic autoantibodies, represented an innovative immunomodulatory approach to a condition predominantly managed by hemodynamic and neurohormonal interventions.

Early clinical development characterized Mibenratide's pharmacokinetic profile, revealing rapid intravenous elimination with a very short, dose-dependent half-life (5.9 to 26.1 minutes). Pharmacodynamic and efficacy data from a small Phase 2 pilot study in patients with dilated cardiomyopathy showed a potential improvement in Left Ventricular Ejection Fraction at one dose level, but this was not consistently supported by other key cardiac biomarkers like NT-proBNP or functional capacity measures. Furthermore, a crucial Phase 2 study designed to directly assess its effects on anti-β1-AR autoantibody levels was withdrawn before completion, leaving a significant gap in understanding its target engagement in patients.

The development of Mibenratide was ultimately discontinued during Phase 2. This decision was likely driven by an unfavorable overall risk-benefit assessment, stemming from a combination of factors: the challenging pharmacokinetic profile requiring frequent IV administration, limited and somewhat inconsistent efficacy signals, and, most critically, significant safety concerns. These safety issues included the development of anti-drug antibodies, with a notable difference in incidence between Caucasian and Japanese healthy volunteers, and the occurrence of serious thromboembolic events (pulmonary embolism and ischemic stroke) in two healthy participants during a Phase 1 study.

Although Mibenratide did not progress to become an approved therapy, its development explored an important and complex area of heart failure pathophysiology. The scientific pursuit of targeting autoimmune mechanisms in cardiac disease continues, and the lessons learned from Mibenratide's journey—regarding peptide drug design, pharmacokinetic optimization, immunogenicity assessment, and the critical importance of early safety signals—can provide valuable insights for future research and development efforts in this challenging therapeutic field.

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