Comprehensive Report on the Investigational Compound LY3872386

I. Executive Summary

LY3872386 was an investigational small molecule compound developed by Eli Lilly and Company, primarily targeting atopic dermatitis. Classified therapeutically as an anti-inflammatory agent for skin disorders, its specific mechanism of action remained undefined throughout its development.1 The compound advanced to Phase 1 clinical evaluation in a multicenter, multifaceted study (NCT06119529) designed to assess its safety, tolerability, and pharmacokinetics in both healthy volunteers and patients with atopic dermatitis.2 However, clinical development was abruptly terminated in July 2024, reportedly due to "emerging nonclinical data".1 This early-stage termination, occurring relatively shortly after trial initiation, suggests the discovery of a significant safety or developability concern in concurrent or newly reviewed nonclinical studies, leading to a swift cessation of human investigation.

II. Introduction to LY3872386

A. Compound Identification and Originator

The investigational drug LY3872386, also referred to as LY 3872386, was under development by Eli Lilly and Company.1 As a novel therapeutic candidate, it represented an effort by a major pharmaceutical entity to address unmet needs in dermatological conditions.

B. Pharmacological Classification

LY3872386 was identified as a small molecule drug.4 Its intended therapeutic applications placed it within the categories of "Anti-inflammatories" and "Skin disorder therapies".1 It was designated as a New Molecular Entity (NME), indicating a chemical structure not previously approved for therapeutic use.1 The compound did not hold Orphan Drug Status.1

C. Mechanism of Action

A notable characteristic of LY3872386 was its officially "Undefined mechanism" of action.1 Publicly accessible databases and development trackers consistently reported no specified molecular target or biochemical pathway through which LY3872386 was intended to exert its effects.4

The absence of a clearly defined or disclosed mechanism of action for a compound entering Phase 1 clinical trials is a significant aspect of its development profile. While proprietary considerations can sometimes lead to delayed disclosure, modern drug development, particularly within large pharmaceutical organizations, typically emphasizes a target-based approach where the molecular interactions are well-characterized before human testing. An undefined mechanism could suggest a discovery pathway based on phenotypic screening, where a desirable biological effect was observed without full elucidation of the underlying molecular target. Such an approach inherently carries a higher risk profile, as predicting the full spectrum of pharmacological effects, potential off-target activities, safety concerns, and drug-drug interactions becomes more challenging. The "emerging nonclinical data" that led to the termination of LY3872386 might have revealed an unfavorable or unviable mechanism, or the lack of mechanistic clarity could have complicated the interpretation of these nonclinical findings. This situation underscores the difficulties that can arise when progressing therapeutic candidates with incompletely understood pharmacological profiles.

Table 1: LY3872386 - Key Compound Characteristics

Characteristic	Details
Investigational Name	LY3872386 (LY 3872386)
Developer	Eli Lilly and Company
Molecular Type	Small Molecule
Therapeutic Class	Anti-inflammatory, Skin disorder therapy
New Molecular Entity	Yes
Mechanism of Action	Undefined
Target Indication	Atopic Dermatitis
Highest Development Phase	Phase 1 (Terminated)

Data compiled from [1]

III. Therapeutic Indication and Rationale

A. Primary Target: Atopic Dermatitis (AD)

The primary therapeutic indication for LY3872386 was atopic dermatitis (AD).1 This was further evidenced by the inclusion of a cohort of participants with atopic dermatitis in its sole Phase 1 clinical trial, NCT06119529.3 Atopic dermatitis is a prevalent chronic inflammatory skin condition characterized by pruritus and eczematous lesions, significantly impacting patients' quality of life. There remains an ongoing need for novel, safe, and effective treatments, particularly oral formulations that can offer convenience and systemic efficacy for moderate-to-severe disease.6

B. Eli Lilly's Interest in Atopic Dermatitis

Eli Lilly and Company has a significant and active presence in the field of immunology, with a particular focus on atopic dermatitis. This is demonstrated by their development and commercialization of biologic treatments such as lebrikizumab (Ebglyss), an IL-13 inhibitor.7 The exploration of LY3872386, a small molecule with an undefined mechanism, likely represented a strategic effort by Lilly to diversify its therapeutic approaches in AD. Small molecules can offer advantages such as oral administration and potentially different mechanisms of action compared to biologic therapies. The development of LY3872386 may have been an attempt to identify novel pathways or targets in AD that could complement or provide alternatives to existing treatments. The early termination of this compound, however, highlights the substantial challenges inherent in pioneering new therapeutic mechanisms, especially for complex, multifactorial inflammatory diseases like atopic dermatitis. This outcome likely signifies the closure of one specific exploratory path within Lilly's broader AD research and development strategy, reinforcing the difficulties associated with advancing novel small molecules when their precise interactions within biological systems are not fully elucidated.

IV. Clinical Development Program: The NCT06119529 Trial

A. Trial Overview

The clinical development of LY3872386 centered around a single Phase 1 study, registered as NCT06119529.1 The official title of the study was "A Study of LY3872386 in Healthy Participants and Participants With Atopic Dermatitis".2 It was also described more extensively as "A Phase 1, Multicenter, Randomized, Placebo-Controlled, Double-Blind, Single-Ascending Dose Study of LY3872386 in Healthy Participants, a Multiple-Ascending Dose Study of LY3872386 in Patients With Atopic Dermatitis, and an Open-Label Multiple-Dose Evaluation of the Safety and Tolerability of Prednisone in Healthy Participants".4 The trial was sponsored by Eli Lilly and Company.2 While its primary purpose was listed as "Basic Science" 3, the main objectives were to evaluate the safety, tolerability, and pharmacokinetics (PK) of single and multiple doses of LY3872386, as well as the safety of prednisone in healthy participants.3

B. Study Design and Methodology

NCT06119529 was a complex, multicenter study. For the LY3872386 arms, the design was randomized, placebo-controlled, and double-blind, while the prednisone arm was open-label.3 The study was structured into three distinct parts:

• Part A: Focused on single ascending doses (SAD) of LY3872386, administered either intravenously (IV) or subcutaneously (SC), compared to placebo in healthy participants. The planned duration for participants in this part was up to approximately 85 days.[3]
• Part B: Designed to evaluate multiple ascending doses (MAD) of LY3872386, also administered IV or SC, versus placebo in participants diagnosed with atopic dermatitis. The planned duration for participants in this part was up to approximately 183 days.[3]
• Part C: Involved the oral administration of multiple doses of prednisone to healthy participants, with a planned duration of up to approximately 44 days.[3] Prednisone, a well-characterized glucocorticoid with anti-inflammatory and immunomodulating properties, likely served as a reference or control for certain assessments.[9]

The target enrollment for the entire study was 18 participants.[2] The study was conducted across multiple international sites, including locations in the United States (California, Florida, Kentucky, Pennsylvania, Texas), Belgium, Hungary, Japan, and the United Kingdom.[2]

The multi-part design of NCT06119529, incorporating SAD and MAD evaluations, both IV and SC routes of administration for LY3872386, and the inclusion of healthy volunteers alongside AD patients, all within a very small target cohort of 18 participants, points to an ambitious and efficient early-phase development strategy. This approach aimed to rapidly gather a broad spectrum of foundational data on safety, tolerability, and PK. The inclusion of a prednisone arm, likely for benchmarking safety or pharmacodynamic markers, further underscores the comprehensive nature of this initial human study. Such complex designs are increasingly utilized to accelerate early development and facilitate quicker go/no-go decisions. However, the subsequent termination indicates that even highly optimized trial designs cannot overcome fundamental issues discovered with the investigational compound itself.

C. Participant Population

The study enrolled adult participants aged 18 to 65 years.3

• Healthy Volunteers (Parts A & C): Participants were required to be "overtly healthy as determined by medical evaluation".[3] A notable feature was the planned inclusion of specific ethnic cohorts:
• First-generation Japanese participants (defined as individuals whose biological parents and all biological grandparents were of exclusive Japanese descent and born in Japan).[3]
• Minimum third-generation Chinese participants (defined as individuals for whom all four biological grandparents were of exclusive Chinese descent and born in China).[3] The body mass index (BMI) range for healthy volunteers was 18.0 to 32.0 kg/m².[3]

The proactive inclusion of distinct Japanese and Chinese ethnic cohorts in such an early and small Phase 1 study is noteworthy. While adding logistical complexity and cost, this approach suggests an intent by Eli Lilly to assess potential ethnic sensitivities in PK or safety from the outset. This is often considered if prior knowledge about the drug class, its metabolic pathways (e.g., involvement of specific CYPs or UGTs with known pharmacogenetic variability), or transporter interactions suggests potential for inter-ethnic differences. Given LY3872386 was a novel small molecule with an undefined mechanism, this could reflect a precautionary measure or an exploratory effort to identify any significant population-specific signals early. The trial's termination due to nonclinical data means that any potential ethnic differences specific to LY3872386 remain unelucidated from this study, but the design itself reflects a growing emphasis on understanding population diversity early in drug development.

• Participants with Atopic Dermatitis (Part B): These participants were required to have a diagnosis of AD for at least 12 months prior to screening. Additionally, they needed a documented history of inadequate response to existing topical medications within the 6 months preceding screening, or a history of failure or intolerance to systemic therapies intended for AD.[3] The BMI range for AD patients was 18.0 to 38.0 kg/m².[3]

Key exclusion criteria for all participants included a known history of diabetes, osteoporosis, current pregnancy or lactation, receipt of live vaccines within 35 days of screening, and a history of multiple or severe allergies or anaphylactic reactions to drugs.[3]

D. Interventions

The investigational product, LY3872386, was administered either intravenously (IV) or subcutaneously (SC).3 A placebo, matching the route of administration of LY3872386, was used as a control.3 In Part C of the study, prednisone was administered orally.3

E. Timeline and Status

The clinical trial NCT06119529 was first posted on clinical trial registries around November 7, 2023.2 The study was anticipated to start or actually started around November 2023 or April 2024, indicating its recent initiation.5

The trial was officially terminated on July 25, 2024.1 Registry updates reflecting this termination were posted around July 23-25, 2024.2 The unequivocal reason cited for the termination was "based on emerging nonclinical data".1

Table 2: Summary of Clinical Trial NCT06119529

Feature	Details
Trial Identifier	NCT06119529
Official Title	A Study of LY3872386 in Healthy Participants and Participants With Atopic Dermatitis
Phase	1
Sponsor	Eli Lilly and Company
Primary Objectives	Evaluate safety, tolerability, and pharmacokinetics of LY3872386 (and safety of prednisone)
Study Design	Multi-part (A, B, C), randomized, placebo-controlled, double-blind for LY3872386; open-label for prednisone
Key Population	Healthy adult volunteers (including specific Japanese and Chinese cohorts); Adult patients with moderate-to-severe atopic dermatitis
Interventions	LY3872386 (IV, SC, single & multiple ascending doses), Placebo (IV, SC), Prednisone (oral, multiple doses)
Target Enrollment	18
Key Dates	First Posted: Nov 2023; Study Start: ~Nov 2023/Apr 2024; Termination: July 2024
Reason for Termination	Emerging nonclinical data

Data compiled from [1]

V. Nonclinical Data and Impact on Development

A. Preclinical Assessment

Preclinical investigations of LY3872386 in the context of atopic dermatitis, utilizing subcutaneous administration in the USA, were noted as occurring prior to November 2023 and were linked to the clinical trial NCT06119529.1 This suggests that the clinical trial registration might have encompassed or been closely tied to ongoing preclinical activities, or that the clinical trial identifier was assigned very early in the development timeline. The definitive termination of the Phase 1 trial was explicitly attributed to "emerging nonclinical data".1

B. Nature of "Emerging Nonclinical Data"

The specific details of the nonclinical findings that precipitated the termination of LY3872386 development have not been publicly disclosed in the available information. Such "emerging nonclinical data" typically refers to new information from animal studies or in vitro experiments that reveals an unacceptable risk or a profile that makes further development unviable. Common reasons for such terminations based on nonclinical data can include, but are not limited to:

• Unexpected organ toxicity (e.g., liver, kidney, cardiac, neurological) observed in ongoing or recently concluded longer-duration toxicology studies in animals.
• Findings related to genotoxicity (damage to DNA), carcinogenicity (potential to cause cancer), or reproductive and developmental toxicity.
• Adverse pharmacological effects or off-target activities that were not predicted or fully understood from earlier, shorter-term studies.
• Unfavorable ADME (Absorption, Distribution, Metabolism, Excretion) properties identified nonclinically that would severely limit the drug's therapeutic potential or safety in humans.

The term "emerging" implies that these data became available after the initial decision to proceed with human clinical trials. This often occurs because certain comprehensive nonclinical studies (e.g., chronic toxicology over several months, carcinogenicity studies spanning up to two years) are initiated concurrently with, or shortly after, the commencement of Phase 1 trials to support later-phase development and longer durations of human exposure. If results from these staggered, longer-term studies reveal significant safety concerns, it can lead to the halting of an active clinical program. The relatively short period (approximately 8-9 months from first posting to termination) during which NCT06119529 was active could align with the timeline for obtaining interim or final results from such nonclinical investigations. This scenario underscores the dynamic and iterative nature of drug development, where nonclinical and clinical assessments are often parallel and interdependent, with new nonclinical findings capable of critically impacting ongoing human trials to safeguard participant safety and optimize resource allocation.

VI. Concluding Assessment

A. Summary of LY3872386's Development Trajectory

LY3872386 was a small molecule New Molecular Entity developed by Eli Lilly and Company, intended for the treatment of atopic dermatitis. A distinguishing feature of its early profile was an undefined mechanism of action. The compound advanced into a Phase 1 clinical trial (NCT06119529), which was designed with considerable complexity to efficiently gather initial safety, tolerability, and pharmacokinetic data across different routes of administration, dosing regimens, and in both healthy volunteers (including specific ethnic cohorts) and patients with atopic dermatitis. Despite this structured approach to early clinical assessment, the development of LY3872386 was short-lived. The Phase 1 trial was terminated in July 2024, less than a year after its initiation, based on unfavorable "emerging nonclinical data."

B. Current Status and Implications

The current development status of LY3872386 is discontinued.4 This cessation, driven by nonclinical findings, signifies the end of Eli Lilly's investigation into this particular compound for atopic dermatitis. While this represents a setback for this specific molecule, Eli Lilly maintains a broader portfolio in immunology and atopic dermatitis, notably with biologic therapies such as lebrikizumab.7 The failure of LY3872386 likely closes one exploratory avenue for a novel small molecule treatment within Lilly's diversified R&D strategy for AD.

For the broader atopic dermatitis therapeutic landscape, the discontinuation of an early-phase compound with an undefined mechanism, like LY3872386, does not immediately alter current treatment paradigms. However, it serves as a pertinent example of the high attrition rates inherent in pharmaceutical research and development, particularly for novel compounds targeting complex inflammatory diseases where the underlying biology is not fully understood or the drug's mechanism is not clearly elucidated. Each such early-stage failure, even when specific details of the adverse nonclinical findings are not publicly available, contributes incrementally to the industry's collective experience and may subtly influence future R&D strategies, reinforcing the importance of robust preclinical characterization and risk assessment before and during early human trials.

VII. References

1 AdisInsight. (2024, August 5). LY 3872386. Springer Nature.

7 Eli Lilly and Company. (2025, March 7). Lilly's EBGLYSS® (lebrikizumab-lbkz) single monthly maintenance injection achieved completely clear skin at three years in half of patients with moderate-to-severe atopic dermatitis [Press release].

2 MedPath. (2024, July 25). A Study of LY3872386 in Healthy Participants and Participants With Atopic Dermatitis.

3 Veeva CTV. (n.d.). A Study of LY3872386 in Healthy Participants and Participants With Atopic Dermatitis. Eli Lilly and Company.

4 Patsnap Synapse. (n.d.). LY3872386.

6 Silverberg, J. I., et al. (2025). Rilzabrutinib, an oral Bruton's tyrosine kinase inhibitor, in moderate-to-severe atopic dermatitis: A phase II, randomized, double-blind, placebo-controlled trial. PubMed.

5 CenterWatch. (2024, July 23). A Study of LY3872386 in Healthy Participants and Participants With Atopic Dermatitis.

8 Eli Lilly and Company. (2024, March 10). More than two-thirds of people with atopic dermatitis and skin of color experienced skin improvement in a first-of-its-kind lebrikizumab study [Press release].

11 Larvol Sigma. (n.d.). NCT06119529: A Study of LY3872386 in Healthy Participants and Participants With Atopic Dermatitis. Eli Lilly and Company.

9 Selleck Chemicals. (n.d.). Prednisolone.

10 CenterWatch. (n.d.). A Study of LY3872386 in Healthy Participants and Participants With Atopic Dermatitis (Page 6, Rash).

4 Patsnap Synapse. (n.d.). LY3872386 (Discontinued).

1 AdisInsight. (2024, August 5). LY 3872386. Springer Nature. 1

7 Eli Lilly and Company. (2025, March 7). Lilly's EBGLYSS® (lebrikizumab-lbkz) single monthly maintenance injection achieved completely clear skin at three years in half of patients with moderate-to-severe atopic dermatitis [Press release]. 7

12 The Dermatology Digest. (2024, April 30). AD Pipeline Update: Eli Lilly Resubmits BLA for Lebrikizumab in AD.

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