ABBV-787: An Investigational CD33-Targeting BET Degrader Antibody-Drug Conjugate for Acute Myeloid Leukemia - Development Overview and Discontinuation

1. Introduction to ABBV-787

1.1. Overview of ABBV-787

ABBV-787 was an investigational therapeutic agent developed by AbbVie, identified by alternative names such as ABBV 787 and ABBV787.[1] It was classified as an Antibody-Drug Conjugate (ADC), a therapeutic modality engineered for the targeted delivery of a cytotoxic payload directly to cancer cells, with the primary route of administration being intravenous.[1] The principal therapeutic area for ABBV-787 was neoplasms, specifically focusing on Hemic and Lymphatic Diseases, with Acute Myeloid Leukemia (AML) as the active indication under investigation during its clinical development phase.[2]

The design of ABBV-787 as an ADC incorporating a degrader payload represented a strategic investment in next-generation targeted oncology therapies. ADCs, by their nature, aim to enhance the therapeutic index of potent cytotoxic agents by minimizing systemic exposure and maximizing drug concentration at the tumor site.[4] The utilization of a protein degrader as the payload component is a further refinement of this strategy. Protein degraders, such as those employed in Proteolysis Targeting Chimeras (PROTACs) which share conceptual similarities with the payloads in Degrader-Antibody Conjugates (DACs), are designed to catalytically induce the elimination of target proteins rather than merely inhibiting their function.[4] This approach holds the potential for increased potency, more durable responses, and the ability to overcome resistance mechanisms often associated with traditional inhibitors. Consequently, the combination of ADC-mediated targeting with the novel mechanism of a degrader payload, as seen in ABBV-787, signifies a sophisticated and potentially more efficacious approach to cancer therapy, reflecting a broader industry trend towards increasingly complex and highly targeted oncological agents.

1.2. Developer

ABBV-787 was developed by AbbVie, Inc., a global specialty biopharmaceutical company headquartered in North Chicago, Illinois, with Richard A. Gonzalez noted as CEO.[1] AbbVie is known for its focus on discovering, developing, manufacturing, and commercializing therapies for chronic and complex diseases, with a significant commitment to oncology.[3] The company maintains a broad and active oncology portfolio and is dedicated to advancing its pipeline, which includes a variety of therapeutic modalities such as ADCs.[5]

The development of ABBV-787 aligns with AbbVie's articulated strategic interest in advancing oncology treatments and specifically in exploring the potential of ADCs.[9] The eventual discontinuation of ABBV-787's development for AML, which will be detailed later in this report, may reflect the rigorous process of portfolio prioritization common within large pharmaceutical research and development organizations. Such decisions are often influenced by a multitude of factors, including emerging clinical data, the competitive landscape, and evolving strategic priorities, particularly in a dynamic field like ADCs where AbbVie possesses multiple assets.[9] Reports in early 2024 indicated that AbbVie was undertaking a "cancer pipeline cull," involving the discontinuation or deprioritization of several early-stage ADCs.[10] While ABBV-787 was not explicitly named in those particular reports, its subsequent discontinuation is consistent with this pattern of active portfolio management and stringent evaluation of early-stage candidates. Furthermore, AbbVie's strategic moves, such as the acquisition of ImmunoGen (an ADC-focused company), would invariably lead to a comprehensive review and potential consolidation of its ADC programs, potentially impacting assets like ABBV-787.[9]

Table 1: ABBV-787 - Key Drug Profile

Attribute	Details	Source Document(s)
Official Name	ABBV-787	1
Alternative Names	ABBV 787, ABBV787	1
Developer	AbbVie, Inc.	1
Drug Class/Modality	Antibody-Drug Conjugate (ADC)	1
Mechanism of Action (Outline)	CD33-targeted delivery of a BET protein degrader	2
Target Antigen	CD33 (Myeloid cell surface antigen CD33)	1
Payload Type	BET (Bromodomain and Extra-Terminal domain) protein degrader	3
Route of Administration	Intravenous	1
Primary Investigated Indication	Acute Myeloid Leukemia (AML), Relapsed/Refractory	1
Highest Development Phase Reached	Phase 1 (Discontinued for AML)	1

2. Mechanism of Action

2.1. Molecular Target: CD33

The therapeutic strategy of ABBV-787 was predicated on its monoclonal antibody component, which was designed to specifically target the CD33 antigen.[1] CD33, also known as myeloid cell surface antigen CD33, is a transmembrane sialic acid-binding immunoglobulin-like lectin (Siglec). Its expression is predominantly found on the surface of myeloid lineage cells, including myeloid leukemia cells, as well as on normal non-pluripotent hematopoietic stem cells and myeloid progenitors.[11] This expression profile, particularly its presence on leukemic blasts in AML, has rendered CD33 an attractive target for antibody-based therapies for several decades.

CD33 is a well-established target in the context of AML, with therapies such as gemtuzumab ozogamicin (an ADC) having previously received regulatory approval. The continued interest in CD33, exemplified by the development of ABBV-787, suggests that while validated, the full therapeutic potential of targeting this antigen may not yet be optimally realized. The approach of combining CD33-directed targeting with a novel payload, specifically a BET protein degrader, represented an innovative strategy. This aimed to potentially improve upon existing CD33-directed therapies by introducing a distinct mechanism of cytotoxicity, potentially offering enhanced efficacy, a more favorable toxicity profile, or the ability to overcome mechanisms of resistance that may have limited earlier agents.

2.2. Payload: BET Protein Degrader

ABBV-787 was engineered as an ADC conjugated to a potent payload designed to degrade Bromodomain and Extra-Terminal domain (BET) proteins.[3] The BET family of proteins, which includes BRD2, BRD3, BRD4, and the testis-specific BRDT, are epigenetic readers that play critical roles as transcriptional co-activators.[11] They are fundamentally involved in regulating the expression of a wide array of genes essential for cellular processes such as proliferation, survival, and differentiation. In many types of cancer, including hematological malignancies like AML, BET proteins are frequently overexpressed or hyperactivated, contributing to oncogenesis by driving the expression of key oncogenes (e.g., MYC) and survival factors.[11] For instance, studies in other cancer types, such as basal breast cancer, have shown that high expression of BET genes correlates with poorer survival outcomes, and treatment with a pan-BET degrader (ZBC260) led to reduced levels of BET proteins and the key downstream oncogene MYC.[13]

The therapeutic potential of targeting BET proteins is significant. While BET inhibitors have been developed and have shown some clinical activity, the strategy of degrading BET proteins, as intended with the ABBV-787 payload, offers potential advantages. Protein degradation can lead to a more profound and sustained depletion of the target protein compared to inhibition, which often requires continuous drug exposure to maintain target occupancy. Degradation may also be effective against scaffolding functions of proteins that are not amenable to inhibition and could potentially overcome resistance mechanisms that arise from mutations in the inhibitor binding site or target overexpression. Although one source indicated "Novel Mechanism: No" for ABBV-787 [1], this likely refers to the CD33 targeting aspect being previously explored, rather than the specific combination of CD33 targeting with a BET degrader payload within an ADC framework, which represents a more novel therapeutic concept.

2.3. Mode of Action

The proposed mode of action for ABBV-787 is a sophisticated, multi-step process characteristic of targeted ADCs, specifically those employing degrader payloads:

1. Target Binding: The monoclonal antibody component of ABBV-787 was designed to selectively bind to the CD33 antigen expressed on the surface of myeloid leukemia cells.[11]
2. Internalization: Following binding to CD33, the ADC-antigen complex was expected to be internalized by the cancer cell, typically through receptor-mediated endocytosis.[11]
3. Payload Release: Once inside the cell, within the endosomal or lysosomal compartments, the BET degrader payload was designed to be released from the antibody, often through the cleavage of a specialized linker connecting the antibody and the payload.[11]
4. BET Protein Degradation: The released BET degrader payload would then engage BET proteins and, through a mechanism described as "as of yet not fully elucidated" [11], recruit components of the cell's own ubiquitin-proteasome system (UPS). This hijacking of the UPS leads to the ubiquitination and subsequent proteasomal degradation of the targeted BET proteins.[11]
5. Downstream Effects: The degradation of BET proteins results in the dysregulation of gene expression, critically leading to the downregulation of key growth-promoting and survival genes, such as MYC.[11] This disruption of essential transcriptional programs was intended to inhibit the proliferation and induce apoptosis in the CD33-expressing, BET-dependent tumor cells.

This intricate mechanism aligns with the broader concept of Degrader-Antibody Conjugates (DACs), which represent an evolution of ADC technology by combining the specificity of antibody-based targeting with the potent and often catalytic action of PROTAC-like degrader payloads.[4] While this multi-step targeted protein degradation pathway offers the potential for high specificity and potent anti-tumor activity, its complexity also introduces multiple points at which efficacy could be compromised or unintended toxicities could arise. Each step—including antibody affinity and specificity, rate and efficiency of internalization, linker stability in circulation versus cleavage intracellularly, payload potency and cell permeability, and the efficiency of engaging the ubiquitin-proteasome system—is a critical determinant of the overall therapeutic outcome. The notation that part of the payload's action was "not fully elucidated" suggests that even during early development, some molecular intricacies of this novel payload's function within the cell were still under active investigation.

3. Therapeutic Rationale in Acute Myeloid Leukemia (AML)

3.1. Target Indication: Relapsed/Refractory (R/R) AML

ABBV-787 was primarily investigated for the treatment of adult patients with relapsed or refractory (R/R) Acute Myeloid Leukemia.[3] This specific patient population represents a significant unmet medical need in oncology. Patients with R/R AML have typically experienced disease progression despite one or more lines of prior therapy, or their disease has failed to respond to initial treatments. The Phase 1 clinical trial NCT06068868, for example, was designed for adult subjects with R/R AML who had been treated with up to three prior lines of therapy and were considered refractory to, or intolerant of, all established AML therapies known to provide clinical benefit.[12]

The focus on R/R AML highlights the aggressive nature of this malignancy and the limited durable treatment options available once standard therapies have failed. Prognosis for these patients is generally poor, and there is a continuous search for novel therapeutic agents that can offer improved outcomes. The development of investigational drugs like ABBV-787, with distinct mechanisms of action, is critical in addressing this therapeutic gap.

3.2. Scientific Basis

The scientific rationale for developing ABBV-787 for AML was rooted in a dual-targeting strategy:

1. CD33 Expression for Targeted Delivery: The consistent expression of the CD33 antigen on the surface of AML blasts provides a molecular handle for antibody-mediated targeted delivery of the therapeutic payload.[11] This allows for preferential accumulation of the cytotoxic agent within the leukemic cells, potentially sparing normal cells that do not express CD33 or express it at significantly lower levels.
2. BET Protein Dependency for Cytotoxicity: AML cells, like many other cancer cells, often exhibit a strong dependency on the activity of BET proteins for their proliferation, survival, and the maintenance of their malignant phenotype. BET proteins regulate critical oncogenic transcriptional programs in AML.[11] Therefore, the degradation of these essential proteins by the ADC's payload was hypothesized to induce potent anti-leukemic effects.

The combination of these two elements—CD33-guided delivery and BET protein degradation—formed the core therapeutic hypothesis for ABBV-787 in AML. The success of such a strategy would inherently depend on several factors: the consistent and sufficiently high expression of CD33 across diverse AML patient blasts to ensure adequate drug delivery, the effective internalization and payload release kinetics, and a significant functional dependency of the targeted leukemic cells on BET protein activity. While BET proteins are generally important in AML, the degree of dependency can vary among AML subtypes and individual patients, which could influence therapeutic response.

4. Clinical Development Program for ABBV-787 in AML

4.1. Overview of Clinical Trials

ABBV-787 advanced into Phase 1 clinical development for the treatment of AML.[1] However, its development for this indication has since been discontinued, with the highest phase reached noted as Phase 1.[2]

4.2. Key Phase 1 Trial: NCT06068868 (M23-477)

The cornerstone of ABBV-787's clinical investigation in AML was the Phase 1 trial identified as NCT06068868, with the sponsor protocol number M23-477.[12]

• Title: "A Phase 1 First-in-Human Study Evaluating Safety, Pharmacokinetics and Efficacy of ABBV-787 in Adult Subjects With Acute Myeloid Leukemia (AML)".[12]
• Design: This was a first-in-human (FIH), open-label, dose-escalation study. The primary aim of such studies is typically to determine the safety profile, identify dose-limiting toxicities (DLTs), establish the maximum tolerated dose (MTD), and characterize the pharmacokinetic (PK) profile of the investigational drug.[12] Approximately 60 adult participants were planned for enrollment across multiple international sites.[14] Participants were to receive ABBV-787 via intravenous (IV) infusion.[14]
• Objectives: The primary objectives focused on evaluating the safety and pharmacokinetics of ABBV-787 and determining its MTD. Preliminary efficacy was also an objective to be assessed.[12]
• Patient Population: The trial enrolled adult subjects with R/R AML who had received up to three prior lines of therapy and were refractory to, or intolerant of, all established AML therapies known to provide clinical benefit.[12] Key inclusion criteria included an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and a white blood cell (WBC) count below 25×109/L prior to study drug initiation. Notable exclusion criteria comprised prior CD33-targeting therapy within 3 months of the first dose of ABBV-787, stem cell transplantation within 3 months, recent anticancer therapy (within 14 days or 5 half-lives), and a history of documented pneumonitis requiring systemic steroids within the last 6 months, or any evidence of active pneumonitis.[12]
• Status: The NCT06068868 trial has been Terminated.[2] The Victorian Cancer Trials Link database indicated its status as "Closed (no longer recruiting)" with a last update on March 7, 2025.[15] Medpath reported the trial as terminated with a posting date of October 5, 2023 [17], and Veeva Systems also lists the trial status as "Terminated".[16]
• Reason for Termination: The specific reasons for the termination of the NCT06068868 trial are not provided in the available documentation.
• Results: No specific efficacy or detailed safety results from this terminated Phase 1 trial for ABBV-787 have been disclosed in the provided source materials. References to safety and efficacy often pertain to other drugs or are general descriptions of trial objectives.[14]
• Locations: The trial was multinational, with planned or active sites in the United States, Japan, Australia, and Israel.[2]

The early termination of a FIH Phase 1 trial, such as NCT06068868, often implies that significant hurdles were encountered during the initial stages of clinical investigation. Phase 1 studies are crucial for establishing a foundational understanding of a new drug's behavior in humans, primarily its safety and tolerability across escalating doses. Termination at this juncture can be due to a variety of factors, including unacceptable toxicity at doses too low to anticipate efficacy, unfavorable pharmacokinetic properties that render the drug difficult to administer or predict, early signals of futility, or strategic company decisions. The absence of publicly reported reasons or detailed clinical results from this trial is common for discontinued early-phase assets but leaves the precise cause of termination undetermined.

4.3. Expanded Access Program (EAP): NCT06439966

An Expanded Access Program (EAP) for ABBV-787 was registered under the identifier NCT06439966.[2]

• Title: "Expanded Access to ABBV-787".[2]
• Purpose: The stated purpose of this EAP was to provide access to ABBV-787 for eligible participants with AML who were not eligible for enrollment in an ABBV-787 clinical trial, prior to potential regulatory approval.[19]
• Status: Various sources list the status of this EAP differently. Synapse by Patsnap and Medpath indicate "Available" [2], while ClinConnect reports it as "Launched May 28, 2024" and "Available".[20] Veeva Systems lists the phase as "Not Applicable".[19]
• Eligibility: Access under this program was intended for patients not eligible for an ABBV-787 clinical trial, with the treating physician responsible for determining if the potential benefit outweighed the risks.[19]

The "Available" status of an EAP, reportedly launched in May 2024 [20], is notably discordant with the termination of the primary Phase 1 clinical trial (NCT06068868, potentially as early as October 2023 [17]) and the overall "Discontinued" status of the ABBV-787 program for AML.[2] This discrepancy could arise from several factors: administrative delays in updating EAP trial registry information; the EAP having been initiated before the definitive decision to discontinue the entire AML program for ABBV-787 was finalized or broadly communicated; or the EAP being intended for a very limited, specific compassionate use scenario, though this is less typical for a drug at such an early stage of development. AbbVie's general policy on pre-approval access states that, in general, only investigational products that are part of existing or planned clinical trials would be considered.[21] Given the termination of the main clinical trial and the discontinuation of the drug for AML, it is highly improbable that this EAP is actively enrolling new patients or providing widespread access to ABBV-787. The EAP's listed status likely does not reflect the current reality of the drug's development trajectory.

4.4. Phase 1 Trial in Japan: jRCT2021230042

A separate Phase 1 clinical trial for ABBV-787 in AML was registered in Japan under the identifier jRCT2021230042.[1]

• Status: This trial is listed with a status of "Not yet recruiting".[1]
• Indication: Acute Myeloid Leukemia.[1]
• Phase: P1 (Phase 1).[1]
• Primary Completion Date: A distant primary completion date of March 16, 2029, is noted.[1]

Considering the termination of the global lead Phase 1 study (NCT06068868) and the overall discontinuation of ABBV-787's development for AML by AbbVie [2], it is highly improbable that the jRCT2021230042 trial will proceed to recruitment. The "Not yet recruiting" status, coupled with a far-off projected completion date, likely reflects initial planning stages that predated the decision to halt the program. It is standard pharmaceutical development practice to suspend or cancel ancillary or regional trials if a lead global trial for an early-stage investigational compound is terminated due to significant safety concerns, lack of efficacy, unfavorable pharmacokinetics, or overarching strategic decisions. Therefore, the jRCT2021230042 trial is unlikely to be initiated.

Table 2: Clinical Trial Overview for ABBV-787 in AML

Trial Identifier	Phase	Title/Brief Description	Status (with date if available)	Target Population	Key Objectives	Geographic Regions	Source Document(s)
NCT06068868 (M23-477)	Phase 1	First-in-Human Study Evaluating Safety, Pharmacokinetics and Efficacy	Terminated (per 17: Oct 5, 2023; per 15: "Closed (no longer recruiting)" Mar 7, 2025)	Adult R/R AML (up to 3 prior lines)	Safety, PK, MTD, Efficacy	US, Japan, Australia, Israel	2
NCT06439966	EAP (Not Applicable Phase)	Expanded Access to ABBV-787	Available/Launched (per 20: May 28, 2024)	Patients not eligible for clinical trial	Provide pre-approval access	Dependent on territory	2
jRCT2021230042	Phase 1	Phase 1 study in AML	Not yet recruiting (Primary completion: Mar 16, 2029)	Acute Myeloid Leukemia	(Presumably safety, PK, MTD)	Japan	1

5. Development Status and Context

5.1. Confirmation of Discontinuation for AML

The clinical development of ABBV-787 for the treatment of Acute Myeloid Leukemia has been definitively discontinued by AbbVie. This is evidenced by its status as "Discontinued Phase 1" in drug development databases.[2] Further supporting this conclusion is the absence of ABBV-787 from AbbVie's publicly disclosed active oncology pipeline, as of May 22, 2025.[9] While some clinical trial registries may show lagging information, such as the "Not yet recruiting" status for the Japanese trial jRCT2021230042 (last updated March 6, 2025, in one source [1]), the combination of an explicit discontinuation notice and omission from the current company pipeline provides strong confirmation that ABBV-787 will not be pursued further by AbbVie for AML.

5.2. Context from AbbVie's Oncology Pipeline Strategy

The discontinuation of ABBV-787 appears to be part of a broader strategic management of AbbVie's extensive oncology pipeline, which includes a significant number of ADCs.[9] Reports emerging in early 2024 described a "cancer pipeline cull" at AbbVie, wherein several early-stage investigational assets, including some ADCs, were discontinued or deprioritized as part of portfolio optimization efforts.[10] Although ABBV-787 was not specifically named in the lists provided in those reports, its early-stage discontinuation aligns with this pattern of rigorous evaluation and strategic pruning of the pipeline.

Furthermore, AbbVie's strategic landscape in ADC development was notably reshaped by its acquisition of ImmunoGen (an ADC-focused company whose assets like ELAHERE and IMGN151 are now part of AbbVie's pipeline [9]), a development that was anticipated around the time of these pipeline adjustments.[10] Such acquisitions typically trigger a comprehensive review of existing internal programs to ensure alignment with the new, combined portfolio and to eliminate redundancies or less competitive assets. The decision to discontinue ABBV-787, an early-stage ADC, could therefore have been influenced by comparative assessments against other internal or newly acquired ADC programs, the overall strategic fit, or a generally high threshold for advancing early-phase candidates in the highly competitive field of oncology. Early-phase drug development is characterized by high attrition rates, and discontinuations can arise from a complex interplay of scientific, clinical, strategic, and commercial considerations.

5.3. Lack of Publicly Reported Clinical Data

A thorough review of the provided documentation reveals no specific safety or efficacy data from the terminated Phase 1 trial NCT06068868 for ABBV-787.[14] This absence of detailed clinical results is a common occurrence for investigational drugs that are discontinued during early-stage development. Pharmaceutical companies are generally not obligated to publish comprehensive results from terminated Phase 1 trials unless there are significant safety findings that have implications for public health or for other drugs in the same class. This lack of publicly available data creates an information gap, making it challenging to ascertain the precise reasons—be they related to safety, pharmacokinetics, early signs of insufficient efficacy, or other factors—that led to the cessation of ABBV-787's development for AML.

6. Preclinical Foundation (Brief Overview)

6.1. Rationale from Mechanism

The preclinical rationale for ABBV-787 was built upon the established roles of its molecular target and payload mechanism. CD33 is a known surface marker on myeloid cells, including AML blasts, making it a suitable anchor for targeted therapy.[11] BET proteins are critical transcriptional regulators, and their dysregulation is implicated in the proliferation and survival of various cancer cells, including those in AML.[11] The concept of targeted protein degradation, as facilitated by ADCs with degrader payloads (or DACs), has strong preclinical support, offering the potential for improved potency and the ability to overcome resistance mechanisms associated with traditional inhibitors.[4] Preclinical studies with other BET degraders, such as ZBC260 in breast cancer models, have demonstrated effective reduction of BET proteins and downstream oncogenic targets like MYC, thereby supporting the biological plausibility of the payload's intended action.[13]

While the scientific premise for a CD33-targeting BET degrader ADC like ABBV-787 is robust on paper, the translation of such complex biological concepts into a safe and effective clinical therapy presents substantial challenges. The discontinuation of ABBV-787 at an early clinical stage suggests that, in this specific instance, the promising preclinical hypotheses did not successfully translate into a viable clinical candidate for AML. This outcome is not uncommon in drug development, where many agents with strong preclinical backing may fail due to unforeseen toxicities, unfavorable pharmacokinetic profiles in humans, or a lack of efficacy in the complex biological context of human disease.

6.2. Specific Preclinical Data for ABBV-787

The provided source materials do not contain specific, detailed preclinical study results for ABBV-787 itself, such as its in vitro potency against AML cell lines, in vivo efficacy in AML animal models, or comprehensive preclinical safety pharmacology. While the NCI Drug Dictionary entries describe the intended mechanism and potential therapeutic activity of ABBV-787 [11], they do not present experimental preclinical data specific to this compound. Other snippets referencing preclinical data [24] pertain to different investigational agents. This gap in publicly available, specific preclinical detail for ABBV-787 limits a full external assessment of its pre-Phase 1 characteristics and the strength of the data package that supported its entry into human trials. Such information, if publicly disclosed, would typically be found in early scientific publications or patent applications.

7. Regulatory Designations

7.1. Orphan Drug Designation (ODD) / Other Designations

Based on the information available in the provided documents, there is no indication that ABBV-787 received Orphan Drug Designation (ODD) from regulatory authorities such as the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA) for the treatment of AML. Similarly, no information suggests that ABBV-787 was granted any other special regulatory designations, such as Breakthrough Therapy Designation or Fast Track status. References to ODD in the source materials (e.g., for erlotinib or venetoclax [22]) pertain to other pharmaceutical compounds, not ABBV-787.

The absence of such special regulatory designations, if indeed ABBV-787 did not receive them, could be due to several factors. ODD is typically sought relatively early in the development process for drugs intended for rare diseases like AML. If ABBV-787 encountered significant challenges or was deprioritized very early in its development trajectory, an application for ODD might not have been submitted, or it may not have reached a stage of data maturity sufficient to support such a designation. Alternatively, the initial data might not have met the specific criteria required by regulatory agencies for these expedited pathways.

8. Conclusion

8.1. Synthesis of ABBV-787 Profile and Development

ABBV-787 was an investigational antibody-drug conjugate developed by AbbVie. It was designed to target the CD33 antigen, which is expressed on acute myeloid leukemia cells, and deliver a potent BET protein degrader payload. The sophisticated mechanism of action involved antibody-mediated targeting, internalization into cancer cells, release of the payload, and subsequent degradation of BET proteins via the ubiquitin-proteasome system, aiming to disrupt essential gene expression programs and inhibit leukemic cell proliferation. The primary indication for ABBV-787 was relapsed/refractory AML, a condition with a high unmet medical need.

8.2. Discontinuation and Implications

The clinical development of ABBV-787 for AML was terminated during Phase 1, as evidenced by the status of its lead clinical trial (NCT06068868) and its confirmed discontinuation from AbbVie's active development pipeline. The precise reasons for this discontinuation have not been made publicly available through the provided documentation. Consequently, the status of ancillary programs, such as the Expanded Access Program (NCT06439966) and the planned Japanese Phase 1 trial (jRCT2021230042), are highly likely to be superseded by the overall termination of the drug's development for AML, rendering their progression improbable.

8.3. Reflection on ADC and AML Drug Development

The trajectory of ABBV-787 underscores the inherent risks and high attrition rates characteristic of early-phase oncology drug development. This holds true even for therapeutic candidates that employ advanced modalities like ADCs and incorporate novel mechanistic approaches such as targeted protein degradation. Despite a strong scientific rationale, translating complex biological concepts into clinically successful therapies remains a formidable challenge.

The discontinuation of ABBV-787 may reflect a confluence of factors. These could range from specific issues encountered in the Phase 1 trial, such as unacceptable toxicity (potentially related to the CD33 target being present on some normal hematopoietic cells, or off-target/on-target toxicities of the BET degrader payload), unfavorable pharmacokinetic properties, insufficient preliminary efficacy signals at tolerable doses, or challenges related to the manufacturing or stability of such a complex biologic. Without access to the specific clinical data, a definitive cause cannot be pinpointed. However, the outcome serves as a reminder that even innovative and well-designed therapeutic strategies must navigate the rigorous empirical testing of clinical trials, where unforeseen biological complexities in humans can derail promising preclinical findings. The competitive and rapidly evolving landscape of both AML therapeutics and ADC technology further intensifies the scrutiny applied to pipeline candidates, likely contributing to stringent decision-making regarding their continued development.

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