TLN-254: An Investigational Oral Agent for Relapsed/Refractory T-Cell Lymphomas

1. Introduction to TLN-254

Overview: TLN-254 is an investigational small molecule drug candidate administered orally, currently undergoing early-stage clinical evaluation for the treatment of various hematologic malignancies, with a particular emphasis on T-cell lymphomas.[1] As an investigational agent, TLN-254 has not yet received marketing authorization from regulatory agencies such as the U.S. Food and Drug Administration (FDA).[2] The development of TLN-254 is being spearheaded by Treeline Biosciences, Inc..[1]

Therapeutic Area: The primary therapeutic focus for TLN-254 is within oncology, specifically targeting relapsed or refractory (R/R) T-cell lymphomas.[1] This group of diseases includes challenging conditions such as Peripheral T-cell Lymphoma (PTCL), Anaplastic Large Cell Lymphoma (ALCL), and Cutaneous T-cell Lymphoma (CTCL), encompassing subtypes like Sézary syndrome and mycosis fungoides.[1] T-cell lymphomas are characterized by their aggressive nature and often poor prognoses, particularly in patients whose disease has returned after prior treatments or has become resistant to standard therapies. The consistent targeting of these R/R T-cell lymphoma populations across the early development program for TLN-254 [1] signals a deliberate strategic effort by Treeline Biosciences. This focus aligns with the company's stated mission of addressing "difficult to drug" targets in areas of significant unmet medical need.[14] By concentrating on these hard-to-treat cancers, Treeline Biosciences appears to be leveraging its scientific approach to make a meaningful clinical impact where existing therapeutic options are limited.

Formulation and Administration: TLN-254 is being developed as an oral tablet.[1] This route of administration offers potential advantages over intravenous therapies, including improved patient convenience, the possibility of outpatient treatment regimens, and potentially better adherence for long-term or maintenance therapy.

2. Mechanism of Action and Preclinical Rationale

The precise molecular target and direct mechanism of action (MoA) for TLN-254 have not been explicitly disclosed in the available public domain information. Several sources categorize the drug type or mechanism as "Unknown" or do not specify it.[7] This is a common practice for investigational compounds in early development stages, as companies often maintain confidentiality regarding proprietary aspects of their novel agents. However, an examination of Treeline Biosciences' recent research activities and patent portfolio provides a strong basis for a plausible hypothesis regarding TLN-254's MoA.

Treeline Biosciences' Focus on BCL6 Degraders: A Potential Link to TLN-254

A significant area of research and development for Treeline Biosciences involves the targeting of B-cell lymphoma 6 (BCL6) using novel protein degradation technology. BCL6 is a transcriptional repressor protein that plays a critical role in the normal development of germinal center B-cells. However, its aberrant or sustained overexpression is a well-documented oncogenic driver in a variety of hematologic malignancies, including diffuse large B-cell lymphoma (DLBCL) and other B-cell lymphomas. BCL6 promotes lymphomagenesis by suppressing genes involved in DNA damage response, cell cycle control, and apoptosis, thereby facilitating uncontrolled cell proliferation and survival.[15] Due to its nature as a transcription factor lacking a well-defined enzymatic pocket, BCL6 has historically been considered a challenging, or "difficult-to-drug," target for conventional small molecule inhibitors.[15]

Treeline Biosciences has actively pursued the development of BCL6-targeting agents. Inventors affiliated with the company (K. M. Oberg, J. D. Hansen, M. D. Correa, T. J. Marrone, M. H. McNeill, M. A. Nagy, K. D. Schleicher, and A. Valiere) are named on recent patent applications (WO 2025/049964 A1, WO 2025/049968 A1, and WO 2025/050016 A1, published March 6, 2025, with priority dates from 2023 and 2024) that describe novel bifunctional BCL6 degraders.[16] These patents are assigned to Treeline Biosciences, Inc..[16] These degraders are a type of Proteolysis Targeting Chimera (PROTAC). PROTACs are heterobifunctional molecules designed to recruit a target protein (in this case, BCL6) to an E3 ubiquitin ligase (such as Cereblon, CRBN), leading to the polyubiquitination of the target protein and its subsequent degradation by the proteasome.[15] This approach offers a distinct advantage over traditional inhibitors as it aims to eliminate the target protein entirely, potentially leading to a more profound and durable biological effect and overcoming resistance mechanisms associated with inhibitor-based therapies.

Preclinical data presented in these patent documents for Treeline's BCL6 degraders are noteworthy:

• Potency and Selectivity: The compounds demonstrated high degradation efficiency, achieving low nanomolar half-maximal degradation concentrations (DC50​) in BCL6-positive cancer cell lines (e.g., DB, DOHH2, OCI-Ly1, SU-DHL-6). Importantly, they exhibited exceptional selectivity for BCL6 over other structurally similar proteins, including GSPT1, IKZF1, IKZF2, IKZF3, and CK1α, which is crucial for minimizing potential off-target toxicities.[15]
• In Vivo Efficacy: In patient-derived xenograft (PDX) and cell line-derived xenograft (CDX) models of BCL6-positive cancers, these degraders induced significant tumor regression (over 50%), even at low doses, and demonstrated sustained tumor suppression.[15]
• Therapeutic Potential in T-Cell Lymphomas: Crucially, the patent literature explicitly highlights the therapeutic potential of these BCL6 degraders in T-cell lymphomas, including ALCL, PTCL, and CTCL.[15] These are the precise indications for which TLN-254 is currently being investigated in clinical trials.
• Oral Bioavailability: The patented BCL6 degraders are reported to possess high oral bioavailability and favorable metabolic stability, supporting their development as oral therapeutic agents.[15] This aligns perfectly with the oral tablet formulation of TLN-254.

The convergence of several lines of evidence strongly suggests that TLN-254 is likely a BCL6 degrader from Treeline Biosciences' proprietary platform. Treeline's stated focus on "difficult-to-drug" targets [14], the nature of BCL6 as such a target, the company's recent and highly relevant patent filings for orally bioavailable BCL6 PROTACs, the documented preclinical efficacy of these PROTACs in T-cell lymphoma models, the matching indications for TLN-254, and its oral route of administration all point towards this conclusion. The timing of the patent publications (March 2025, with priority dates in 2023-2024) and the initiation of the TLN-254 Phase 1b trial in December 2024 [9] are also consistent with this developmental trajectory. While direct confirmation from the company is pending, the circumstantial evidence is compelling and provides a strong scientific rationale for TLN-254's development in T-cell lymphomas.

Role of Artificial Intelligence (AI) and Machine Learning (ML)

TLN-254 is reported to have been developed utilizing an artificial intelligence (AI) and machine learning (ML) technology platform.[1] Treeline Biosciences explicitly lists computational science as one of its four pillars of drug discovery, employing in silico simulations, AI, and ML to identify chemical scaffolds, predict molecular properties, and optimize drug candidates.[14] The application of AI/ML is particularly relevant for designing complex molecules like PROTACs, which require multiparameter optimization (target binding, E3 ligase binding, linker properties, cell permeability, pharmacokinetic attributes). These computational tools can significantly accelerate the design-make-test-analyze cycle, potentially leading to more rapid identification of candidates with desirable profiles for challenging targets like BCL6.

3. Clinical Development Program: The NCT06733441 Study

The primary clinical investigation for TLN-254 is the NCT06733441 trial, also identified as TLN-254-2401 and NCI-2024-10412.[5]

Table 1: Overview of Clinical Trial NCT06733441

Parameter	Details	Supporting Snippets
Official Title	Phase 1b, Randomized, Dose Optimization Study to Assess the Anti-Tumor Activity, Safety, and Pharmacokinetics of TLN-254 in Patients with Relapsed or Refractory T-cell Lymphoma	7
Phase	Phase 1b	2
Status	Recruiting	2
Sponsor	Treeline Biosciences, Inc.	3
Trial Identifiers	NCT06733441, TLN-254-2401, NCI-2024-10412	2
Key Conditions	Relapsed or Refractory T-cell Lymphoma, including Peripheral T-cell lymphoma (PTCL), Anaplastic large cell lymphoma (ALCL), Cutaneous T-cell lymphoma (CTCL) (Sézary syndrome, Mycosis fungoides), Nodal T-follicular helper (TFH) cell lymphoma (angioimmunoblastic, follicular type, NOS), PTCL NOS	1
Intervention	Drug: TLN-254, oral monotherapy	2
Primary Outcome Measures	Percentage of Participants With Objective Response; Percentage of Participants With Complete Response (CR); Percentage of Participants With Partial Response (PR). Time Frame: Up to 2 years.	9
Secondary Outcome Measures	Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs); Severity of TEAEs (NCI CTCAE v5.0); Plasma concentrations of TLN-254; Duration of Response (DOR). Time Frame: Up to 2 years (TEAEs, SAEs, DOR); PK: Day 1 of Cycle 1 and Day 1 of each even numbered Cycle for up to 2 years (Each Cycle length = 28 days).	9
Estimated Enrollment	50 participants	3
Start Date	December 16, 2024	9
Estimated Primary Completion Date	November 15, 2026	18
Estimated Study Completion Date	November 15, 2028	10

Study Design and Objectives:

The NCT06733441 trial is a Phase 1b, open-label, randomized, dose-optimization study evaluating TLN-254 as a monotherapy.7 The "randomized" component in this early-phase context likely pertains to the assignment of participants to different dose levels or schedules within expansion cohorts, once initial safety parameters have been established in a smaller group, or to different dose optimization arms. The primary objectives are to assess the anti-tumor activity of TLN-254, characterize its safety and tolerability profile, and understand its pharmacokinetics (PK) in patients with R/R T-cell lymphomas. A key goal is the determination of the highest safe dose or the recommended Phase 2 dose (RP2D) to guide future studies.2 The Phase 1b designation suggests that following initial dose escalation to determine maximum tolerated dose (MTD) or identify preliminary active dose ranges, the study will likely expand cohorts at one or more selected dose levels. This expansion allows for more comprehensive safety data collection and preliminary efficacy assessment. The dose optimization aspect implies that different dosing regimens (e.g., varying daily doses or schedules) might be explored to identify an optimal balance between therapeutic effect and tolerability before advancing to larger Phase 2 trials.

Target Patient Population:

The trial enrolls adult patients (18 years of age or older) diagnosed with various subtypes of T-cell lymphoma that have relapsed after, or proven refractory to, prior systemic therapies.1 The study is structured with at least two main cohorts:

• Cohort 1: Patients with Peripheral T-cell Lymphoma (PTCL) that has relapsed after, or not responded to, at least one prior systemic treatment regimen. Eligible PTCL subtypes include Nodal T-follicular helper (TFH) cell lymphoma (angioimmunoblastic type, follicular type, or not otherwise specified), PTCL NOS, Anaplastic Large Cell Lymphoma (ALCL) ALK-positive, and ALCL ALK-negative. A specific requirement for patients with ALCL is prior treatment with brentuximab vedotin, indicating that TLN-254 is being evaluated in a population that has already received a standard targeted therapy for CD30-positive ALCL.[5]
• Cohort 2: Patients with relapsed/refractory Cutaneous T-cell Lymphoma (CTCL) that has relapsed after, or not responded to, at least two prior systemic treatments. Eligible CTCL subtypes include Sézary syndrome and Mycosis fungoides.[1]

The inclusion of a diverse array of T-cell lymphoma subtypes within a Phase 1b trial suggests a strategy to broadly assess the activity of TLN-254. This approach may be driven by a belief that the drug's mechanism of action is relevant across these histologies, or it may serve as an efficient method to identify early signals of efficacy in multiple populations with high unmet needs. Success in specific subtypes could then inform the design of more focused Phase 2 studies.

Key Eligibility Criteria:

• Inclusion Criteria: Participants must be 18 years of age or older, have histologically confirmed R/R T-cell lymphoma as specified for each cohort, possess measurable disease at study entry, have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2, demonstrate adequate organ function, have freshly biopsied or archival tumor tissue available for correlative studies, and agree to adhere to a pregnancy prevention plan.[2]
• Exclusion Criteria: Key exclusions include receipt of systemic anti-cancer treatment within 5 half-lives or 4 weeks prior to the first dose of TLN-254, allogeneic stem cell transplant (SCT) within 90 days or autologous SCT within 60 days prior to study intervention, current or past history of central nervous system (CNS) involvement by lymphoma, any significant acute or chronic medical illness or active uncontrolled infection that would place the participant at unacceptable risk, pregnancy or lactation, and inability to swallow tablets.[2]

Intervention:

Participants in the trial will receive TLN-254 as an oral monotherapy. The specific dose administered will vary depending on the participant's enrollment cohort (reflecting dose escalation stages) and the emerging safety data from the trial.2 Treatment can continue for up to 2 years, and participants will be monitored for health outcomes for up to 2 years.2

Outcome Measures:

• Primary Outcome Measures: The primary efficacy endpoints are focused on anti-tumor activity and include: Percentage of Participants with Objective Response (ORR), Percentage of Participants with Complete Response (CR), and Percentage of Participants with Partial Response (PR). These responses will be assessed for up to 2 years.[9] These are standard and critical measures for evaluating the preliminary efficacy of an oncology drug in early-phase trials.
• Secondary Outcome Measures: Secondary objectives include a comprehensive assessment of safety and tolerability (Number of Participants with Treatment-Emergent Adverse Events and Serious Adverse Events; Severity of TEAEs graded according to NCI Common Terminology Criteria for Adverse Events Version 5.0), characterization of the pharmacokinetic profile of TLN-254 (plasma concentrations measured at predefined timepoints, including Day 1 of Cycle 1 and Day 1 of each even-numbered cycle, with each cycle being 28 days), and assessment of the Duration of Response (DOR) in participants who achieve a CR or PR. These secondary outcomes will also be assessed for up to 2 years.[9]

Current Status, Timelines, and Recruitment:

The NCT06733441 trial is currently active and recruiting participants.2 The trial status reportedly changed from "not yet recruiting" to "recruiting" around December 24, 2024.19

Key timelines associated with the trial are:

• First Posted on ClinicalTrials.gov: December 13, 2024.[4]
• Actual Study Start Date: December 16, 2024.[9]
• Estimated Primary Completion Date: November 15, 2026.[18]
• Estimated Study Completion Date: November 15, 2028.[10] The target enrollment for the study is 50 participants.[3] Currently, the listed recruitment locations in the United States are Memorial Sloan Kettering Cancer Center in New York, New York, and Washington University School of Medicine (affiliated with Siteman Cancer Center) in St. Louis, Missouri.[4]

4. Regulatory Status

TLN-254 is an investigational drug candidate in the early stages of clinical development. As such, it has not yet received marketing approval from the U.S. Food and Drug Administration (FDA) or any other global regulatory health authority.[2]

Information available in the provided research materials does not indicate that TLN-254 has been granted any special regulatory designations by the FDA, such as Orphan Drug Designation, Fast Track Status, or Breakthrough Therapy Designation. Similarly, there is no mention of such designations from the European Medicines Agency (EMA).[6]

The absence of these designations at this early stage of development (Phase 1b) is not unusual. Companies often apply for such statuses once initial clinical data, particularly demonstrating safety and preliminary signals of efficacy in a defined patient population with unmet needs, become available. T-cell lymphomas, as a group and as individual subtypes, frequently meet the criteria for rare diseases, potentially making TLN-254 eligible for Orphan Drug Designation in the future. Should the ongoing NCT06733441 trial yield compelling data regarding safety and efficacy in treating these serious conditions with limited therapeutic options, Treeline Biosciences may pursue Fast Track or Breakthrough Therapy designations to potentially expedite the subsequent development and review processes.

5. Developer Profile: Treeline Biosciences, Inc.

Company Focus and Therapeutic Areas:

Treeline Biosciences, Inc. is a biotechnology company dedicated to the discovery and development of novel therapeutics for cancer and other serious diseases. The company's strategic R&D efforts are concentrated in oncology, hematology, and immunology, with a particular mission to address validated molecular targets that have historically been considered "difficult-to-drug".14

Technology Platforms:

Treeline Biosciences leverages a multi-faceted approach to drug discovery, integrating several advanced technology platforms:

• Artificial Intelligence (AI) and Machine Learning (ML): AI and ML are reportedly integral to the company's drug discovery and development processes, including for TLN-254.[1] This involves using computational tools for in silico simulations to identify chemical scaffolds, predict molecular properties, and optimize drug candidates.
• Advanced Medicinal Chemistry: The company has strong capabilities in medicinal chemistry, employing traditional approaches alongside newer modalities such as allosteric modulation, covalent inhibition, molecular glues, and heterobifunctional degraders (e.g., PROTACs). This diverse chemical toolkit is aimed at expanding the range of druggable targets.[14]
• Integrated Drug Discovery Pillars: Treeline's R&D model is built upon four core pillars: mechanistic biology, medicinal chemistry, computational science, and structural biology & protein science. This integrated structure is designed to foster collaboration and leverage insights across disciplines.[14]

Leadership and Founding:

The company was co-founded by Joshua Bilenker, M.D., who serves as Chief Executive Officer, and Jeff Engelman, M.D., Ph.D., who serves as Chief Scientific Officer.39 Dr. Bilenker was previously the CEO of Loxo Oncology at Lilly, following Eli Lilly's acquisition of Loxo Oncology, a company known for its success in developing precision cancer therapies. Dr. Engelman formerly served as the Vice President and Global Head of Oncology at the Novartis Institutes for BioMedical Research (NIBR). This leadership brings a wealth of experience from both successful biotech ventures focused on targeted oncology and large pharmaceutical R&D environments, suggesting a strategic direction well-versed in navigating the complexities of oncology drug development.

Funding and Resources:

Treeline Biosciences has secured substantial financial backing, enabling its ambitious R&D programs. Notable funding rounds include a Series A financing of $212 million in April 2021, an additional $261.3 million in October 2022, and a further $421 million in October 2024, bringing the total raised to approximately $894.3 million. This significant investment comes from a syndicate of prominent life science investors, including KKR, ARCH Venture Partners, Google Ventures (GV), OrbiMed, Rock Springs Capital, and Access Industries.36 The company operates from sites in San Diego, California; Stamford, Connecticut; and Watertown, Massachusetts.36 This robust financial foundation allows Treeline to pursue long-term, high-risk/high-reward projects and to build comprehensive internal R&D capabilities.

Pipeline Strategy:

While a detailed public pipeline is not extensively disclosed on the company's website 14, Treeline's strategy clearly centers on tackling challenging oncogenic targets. The development of BCL6 degraders, as evidenced by their patent portfolio 15, appears to be a significant component of this strategy, aligning with their mission and technological capabilities. TLN-254 is the most visible clinical-stage asset based on the provided information.

The combined experience of the leadership team, particularly Dr. Bilenker's success with precision medicines at Loxo Oncology and Dr. Engelman's extensive experience at Novartis, positions Treeline Biosciences to effectively identify and prosecute high-value, challenging targets in oncology. Their focus on innovative modalities like protein degraders for targets such as BCL6 reflects this strategic orientation. Furthermore, the substantial capital raised from distinguished investors underscores confidence in the company's vision, team, and technological approach, providing the necessary runway to advance its pipeline through the critical early stages of development.

6. Summary and Future Outlook

TLN-254 is an orally administered, investigational small molecule currently in Phase 1b clinical development by Treeline Biosciences for the treatment of relapsed or refractory T-cell lymphomas. While its precise mechanism of action has not been officially disclosed, substantial evidence from the company's patent portfolio and research focus strongly suggests that TLN-254 may be a B-cell lymphoma 6 (BCL6) protein degrader, utilizing PROTAC technology. This aligns with Treeline's strategy of targeting "difficult-to-drug" oncogenes with novel therapeutic modalities, supported by advanced computational and medicinal chemistry platforms.

The ongoing NCT06733441 clinical trial is a critical step in the development of TLN-254. This study aims to determine the safety, tolerability, pharmacokinetics, and preliminary anti-tumor activity of TLN-254, as well as to identify a recommended Phase 2 dose. The inclusion of a diverse range of T-cell lymphoma subtypes, including various PTCLs, ALCL, and CTCL (mycosis fungoides and Sézary syndrome), will provide valuable insights into the potential breadth of activity of TLN-254.

Significance for T-cell Lymphoma Treatment:

T-cell lymphomas represent a heterogeneous group of hematologic malignancies with often aggressive clinical courses and limited treatment options, especially in the relapsed/refractory setting. If TLN-254 demonstrates significant and durable clinical activity with a manageable safety profile, particularly if it operates via a novel mechanism like BCL6 degradation, it could represent an important new therapeutic option for these patients. The oral route of administration further enhances its potential utility and patient convenience.

Anticipated Next Steps and Milestones:

The near-term development path for TLN-254 will likely involve:

• Completion of the dose escalation and dose optimization phases of the NCT06733441 trial to establish the MTD and/or RP2D.
• Initial data readouts on safety, tolerability, pharmacokinetics, and preliminary efficacy from the ongoing Phase 1b study. The estimated primary completion date for this trial is November 15, 2026.[18]
• Presentation of detailed preclinical data specifically linking TLN-254 to its target and mechanism, alongside emerging clinical data, at major oncology conferences (e.g., ASH, ASCO, EAU, ESMO). Currently, no specific presentations for TLN-254 have been identified in the provided materials.[3]
• Strategic decisions regarding which specific T-cell lymphoma subtype(s) to prioritize for further development in Phase 2 studies, based on the efficacy signals observed in the Phase 1b cohorts.
• Potential submission of applications for regulatory designations such as Orphan Drug Designation, Fast Track Status, or Breakthrough Therapy Designation if the clinical data are compelling and meet the relevant criteria.

The NCT06733441 trial is pivotal not only for TLN-254 but also as an early clinical validation of Treeline Biosciences' drug discovery engine and its capacity to generate novel therapeutics against challenging targets. Positive outcomes from this study would significantly de-risk TLN-254 and bolster confidence in the company's platform technologies.

The field of BCL6 degradation is an active area of oncology research, with other companies also developing BCL6-targeting PROTACs (e.g., Arvinas with ARV-393 [46]). Should TLN-254 indeed be a BCL6 degrader, its clinical performance will be assessed within this evolving competitive and scientific landscape. Key differentiating factors will likely include its specific chemical structure, pharmacokinetic and pharmacodynamic properties, safety profile, and the breadth and depth of its efficacy across various lymphoma subtypes, including both B-cell and T-cell malignancies, as suggested by Treeline's patent claims for their BCL6 degraders.[15] The oral bioavailability of TLN-254 is a notable feature that could offer a competitive advantage. The successful development of TLN-254 would represent a significant advancement for patients with T-cell lymphomas and a validation of Treeline Biosciences' innovative approach to cancer drug discovery.

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