ARV-393: A PROTAC BCL6 Degrader for Non-Hodgkin Lymphoma – Preclinical Profile and Phase 1 Clinical Development

I. Introduction to ARV-393

A. Nomenclature, Class, and Developer

ARV-393 is an investigational, orally bioavailable small-molecule therapeutic agent classified as a PROteolysis TArgeting Chimera (PROTAC) specifically engineered to induce the degradation of the B-cell lymphoma 6 protein (BCL6).[1] The oral bioavailability of ARV-393 is a significant attribute, offering potential for patient convenience and outpatient administration regimens, which can be advantageous compared to intravenously administered therapies. The PROTAC modality itself represents a novel therapeutic strategy, aiming to eliminate target proteins rather than merely inhibiting their function, which may offer distinct advantages in overcoming resistance mechanisms and achieving more profound biological effects.

The development of ARV-393 is being spearheaded by Arvinas Inc., a clinical-stage biotechnology company that has established a prominent position in the field of targeted protein degradation.[2] Arvinas's core technological expertise lies in the design and optimization of PROTAC molecules for various therapeutic targets.

For clarity and comprehensive literature tracking, ARV-393 is also referred to by several alternative designations, including ARV 393, ARV393, PROTAC BCL6 degrader ARV-393, and proteolysis-targeting chimera protein degrader ARV-393.[8]

B. Investigational Status and Therapeutic Intent

ARV-393 is currently undergoing Phase 1 clinical evaluation in the trial NCT06393738. This first-in-human study is actively enrolling patients diagnosed with relapsed or refractory (r/r) non-Hodgkin lymphoma (NHL). The patient population encompasses a range of mature B-cell lymphoma subtypes and, notably, also includes nodal T-follicular helper cell lymphoma, angioimmunoblastic-type (nTFHL-AI), a less common T-cell malignancy where BCL6 is also implicated.[1]

The primary therapeutic intent of ARV-393 is to elicit potent anti-tumor effects in these hematologic malignancies. This is anticipated to be achieved through the targeted degradation and subsequent elimination of the BCL6 oncoprotein, thereby inhibiting tumor growth and potentially inducing tumor regression.[19]

The development of ARV-393 is particularly significant as it addresses a long-standing challenge in oncology: the effective targeting of transcription factors like BCL6. Many transcription factors have been considered "undruggable" by conventional small molecule inhibitors due to their lack of well-defined enzymatic active sites and their reliance on broad protein-protein interaction surfaces.[3] The PROTAC technology employed by ARV-393 circumvents these challenges by not attempting to inhibit BCL6 function directly, but rather by coopting the cell's natural ubiquitin-proteasome system to specifically destroy the BCL6 protein entirely.[1] This approach may offer a more complete and sustained inactivation of the target compared to traditional inhibitors. BCL6, as a master transcriptional regulator controlling hundreds of genes, has multifaceted roles in lymphomagenesis.[3] Its complete removal via degradation could therefore lead to a more profound and durable anti-cancer effect than merely blocking a single functional domain or interaction.

Should ARV-393 demonstrate clinical safety and efficacy, it would not only provide a new therapeutic option for patients with BCL6-driven lymphomas but also serve as a significant validation for the PROTAC platform against this challenging class of oncogenic targets. Such success could stimulate further research and development of PROTAC degraders against other oncogenic transcription factors that have hitherto been considered intractable, potentially broadening the scope of "druggable" targets in cancer therapy.

II. Scientific Rationale and Mechanism of Action

A. BCL6: A Key Transcriptional Repressor and Oncogenic Driver in Lymphoma

B-cell lymphoma 6 (BCL6) is a crucial transcriptional repressor protein belonging to the POZ/zinc finger family. It plays an essential physiological role in the normal development and function of germinal center (GC) B-cells, which are critical sites for antibody affinity maturation and memory B-cell generation.[1] Within the GC microenvironment, BCL6 orchestrates a complex transcriptional program, directly regulating a large cohort of over 600 target genes. Its functions are pivotal for enabling the rapid proliferation and somatic hypermutation processes characteristic of GC B-cells, in part by suppressing key cellular pathways that control cell cycle checkpoints, terminal differentiation programs, apoptosis, and the DNA damage response.[2] This tightly controlled expression of BCL6 is vital for normal immune responses.

However, the dysregulation of BCL6 expression or activity is a common and critical oncogenic event in the pathogenesis of several NHL subtypes. These include diffuse large B-cell lymphoma (DLBCL), which is the most prevalent type of NHL, follicular lymphoma (FL), Burkitt's lymphoma, and, notably, the T-cell malignancy known as nodal T-follicular helper cell lymphoma, angioimmunoblastic-type (nTFHL-AI).[1] In these malignant contexts, sustained or aberrant BCL6 activity contributes to the oncogenic phenotype by promoting cancer cell survival, inhibiting apoptosis, fostering unchecked proliferation, and potentially contributing to genomic instability. For instance, chromosomal translocations involving the BCL6 gene are observed in a significant proportion of FL cases and are associated with an increased risk of transformation into more aggressive forms of lymphoma.[1]

Despite its clear role as an oncogenic driver, BCL6 has historically been considered a challenging, or "undruggable," target for conventional therapeutic intervention with small molecule inhibitors.[3] This difficulty arises primarily from its nature as a transcription factor, which mediates its biological effects predominantly through extensive protein-protein interactions rather than possessing a well-defined enzymatic active site that can be easily targeted by classical occupancy-driven inhibitors.

B. ARV-393: PROTAC-Mediated Degradation of BCL6

ARV-393 is a rationally designed, bifunctional small molecule that embodies the PROTAC strategy to overcome the challenges of targeting BCL6. Its molecular architecture consists of three key components:

1. A high-affinity ligand (binding moiety) that specifically recognizes and binds to the BCL6 protein.
2. A flexible chemical linker of optimized length and composition.
3. A distinct ligand (binding moiety) that recruits an E3 ubiquitin ligase. In the case of ARV-393, this E3 ligase-binding moiety is derived from lenalidomide and targets the cereblon (CRBN) E3 ubiquitin ligase complex.[1]

The mechanism of action of ARV-393 involves a sequence of precisely orchestrated intracellular events:

1. Target Engagement: Upon oral administration and cellular uptake, the BCL6-binding domain of ARV-393 selectively docks with the BCL6 protein within the target lymphoma cell.[8]
2. Ternary Complex Formation: Simultaneously, the CRBN-binding moiety of ARV-393 engages the CRBN E3 ubiquitin ligase. This dual binding event effectively brings the BCL6 protein and the CRBN E3 ligase into close spatial proximity, facilitating the formation of a transient but productive ternary complex (ARV-393:BCL6:CRBN).[1]
3. Ubiquitination: The formation of this ternary complex positions BCL6 as a neo-substrate for the CRBN E3 ligase. CRBN then catalyzes the transfer of ubiquitin molecules from ubiquitin-conjugating enzymes (E2s) to specific lysine residues on the surface of the BCL6 protein. This results in the polyubiquitination of BCL6, which serves as a degradation signal.[1]
4. Proteasomal Degradation: The polyubiquitinated BCL6 protein is subsequently recognized by the cell's endogenous protein degradation machinery, the 26S proteasome. The proteasome unfolds and proteolytically cleaves BCL6 into small peptides, effectively eliminating the protein from the cell.[1]

The ultimate consequence of ARV-393-mediated BCL6 degradation is the abrogation of BCL6-driven transcriptional repression. This leads to the de-repression of BCL6 target genes, many of which are involved in tumor suppressor functions, cell cycle arrest, and apoptosis, thereby inhibiting the survival and proliferation pathways essential for lymphoma cells.[8]

A distinguishing feature of the PROTAC mechanism, and thus of ARV-393, is its potential for catalytic activity. After mediating the ubiquitination of a BCL6 molecule, ARV-393 is released from the ternary complex and can then engage another BCL6 protein and E3 ligase, thereby initiating multiple rounds of degradation. This "iterative activity" [9] means that sub-stoichiometric concentrations of ARV-393 may be sufficient to achieve significant and sustained BCL6 degradation.

The degradation of BCL6 by ARV-393 is anticipated to offer a more comprehensive and profound therapeutic effect compared to traditional BCL6 inhibitors. By physically eliminating the entire BCL6 protein, ARV-393 nullifies all its oncogenic functions, including those mediated by its scaffolding properties and its participation in various protein-protein interaction networks. These aspects of BCL6 biology might remain largely unaffected by conventional inhibitors that target only a specific binding pocket or interaction domain. This is particularly relevant for a master transcriptional regulator like BCL6, which influences a vast array of downstream genes and pathways.[3] The removal of the entire protein ensures a more complete shutdown of its oncogenic signaling network.

The choice of cereblon (CRBN) as the E3 ligase, recruited via a lenalidomide-derived moiety [4], is a well-established strategy in PROTAC development, leveraging a well-characterized component of the ubiquitin-proteasome system. It is worth noting, however, that immunomodulatory drugs (IMiDs) like lenalidomide are known to induce the degradation of specific neosubstrates (e.g., Ikaros, Aiolos) by modulating CRBN. While ARV-393 is designed to specifically direct CRBN towards BCL6, any intrinsic biological effects of the CRBN-binding moiety itself on other CRBN functions or substrates could potentially contribute to the overall therapeutic profile or off-target effects of ARV-393. This aspect warrants consideration in the comprehensive evaluation of the drug's activity and safety.

The catalytic or "iterative" nature of ARV-393's mechanism [9] holds significant therapeutic promise. It suggests that sustained BCL6 degradation and consequent anti-tumor effects might be achievable even if intracellular drug concentrations fluctuate or do not constantly remain at levels required for stoichiometric inhibition by a traditional antagonist. This characteristic could translate into a wider therapeutic window, potentially allowing for more flexible dosing schedules and a reduced risk of dose-limiting toxicities in the clinical setting, while still maintaining robust target engagement and efficacy.

III. Preclinical Profile of ARV-393

A. In Vitro Activity

Laboratory studies have consistently shown that ARV-393 is capable of inducing potent and nearly complete degradation of the BCL6 protein within various lymphoma cell lines.[13] This fundamental activity confirms target engagement and the intended primary mechanism of action at a cellular level. Importantly, this BCL6 degradation directly translates into significant anti-proliferative effects across a panel of diffuse large B-cell lymphoma (DLBCL) and Burkitt's lymphoma cell lines.[13] These findings establish a clear link between the molecular action of ARV-393 (BCL6 protein removal) and a desired functional anti-cancer outcome (inhibition of cancer cell growth) in vitro.

B. In Vivo Monotherapy Efficacy

The anti-tumor activity of ARV-393 as a single agent has been further evaluated in more complex in vivo systems. In patient-derived xenograft (PDX) models of NHL, which are considered to better recapitulate the heterogeneity and microenvironment of human tumors, ARV-393 monotherapy has demonstrated the ability to induce tumor regressions.[1] This observation of tumor shrinkage, as opposed to merely slowing tumor growth, is a strong preclinical indicator of potent anti-cancer activity.

In cell line-derived xenograft (CDX) models of NHL, ARV-393 exhibited dose-responsive tumor growth inhibition. Notably, this anti-tumor effect was shown to directly correlate with the extent of BCL6 degradation within the tumor tissue. Such a correlation was observed in the SU-DHL-4 model, which represents an aggressive "triple-hit" high-grade B-cell lymphoma (characterized by concurrent rearrangements of MYC, BCL2, and BCL6 genes).[1] Efficacy in this particularly aggressive and often treatment-resistant lymphoma subtype underscores the potential of ARV-393.

Further studies involving daily oral administration of ARV-393 for 21 days across a diverse panel of more than 10 different NHL PDX models revealed a spectrum of anti-tumor responses. These responses ranged from complete tumor regressions in some models to partial tumor growth inhibition in others, highlighting the broad monotherapy activity of ARV-393 in BCL6-expressing lymphomas.[13] Ongoing preclinical investigations are expected to further delineate the efficacy spectrum of ARV-393, with anticipated data on its single-agent activity in PDX models of transformed Follicular Lymphoma and nTFHL-AI.[17] These studies will provide additional support for the inclusion of these specific lymphoma subtypes in clinical trials.

C. Preclinical Combination Studies

Recognizing that combination therapies are the cornerstone of lymphoma treatment, extensive preclinical studies have evaluated ARV-393 in conjunction with various standard-of-care (SOC) agents and investigational small molecule inhibitors (SMIs). These data, largely presented at the American Association for Cancer Research (AACR) Annual Meeting in 2025, reveal significant synergistic potential.[3]

1. Combination with Standard-of-Care (SOC) Chemotherapy (R-CHOP): When ARV-393 was combined with the R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), a standard first-line treatment for DLBCL, it induced significantly greater tumor growth inhibition (TGI) compared to R-CHOP alone or ARV-393 monotherapy in aggressive DLBCL and high-grade B-cell lymphoma (HGBCL) models.3 Most strikingly, this combination resulted in complete tumor regressions in all treated mice (100%) in these challenging preclinical models.3 Such profound activity suggests a powerful synergistic interaction that could translate into substantially improved outcomes for patients.
2. Combination with SOC Biologics: ARV-393 also demonstrated synergistic anti-tumor activity when combined with SOC biologic agents commonly used in lymphoma treatment. These include:

• Anti-CD20 antibody: Rituximab
• Anti-CD19 antibody: Tafasitamab
• Anti-CD79b antibody-drug conjugate: Polatuzumab vedotin These combinations led to tumor regressions and significantly stronger TGI than any single agent in the SU-DHL-4 CDX model (representing HGBCL).[3] Specifically, complete tumor regressions were observed in 9 out of 9 mice when combined with rituximab, 4 out of 10 with polatuzumab, and 10 out of 10 with tafasitamab. The combination with tafasitamab showed superior TGI (10/10 regressions) compared to tafasitamab plus lenalidomide (55% TGI).[9]

A key mechanistic insight underpinning the synergy with anti-CD20 therapies is the finding that ARV-393 treatment can lead to increased CD20 protein expression on lymphoma cells.[3] Downregulation or loss of CD20 is a known mechanism of resistance to rituximab and other anti-CD20 agents. By upregulating CD20, ARV-393 may enhance the efficacy of these biologics and potentially overcome resistance. The proposed mechanism involves BCL6 degradation leading to the restoration of CREBBP/EP300 chromatin access, thereby de-repressing CD20 gene transcription.[9] This finding provides a strong molecular rationale for combining ARV-393 with CD20-targeted agents.

3. Combination with Investigational Small Molecule Inhibitors (SMIs): ARV-393 exhibited superior TGI when combined with SMIs that target other clinically validated oncogenic drivers in lymphoma. These combinations include:

• BTK inhibitors (e.g., acalabrutinib)
• BCL2 inhibitors (e.g., venetoclax)
• EZH2 inhibitors (e.g., tazemetostat) These combinations resulted in tumor regressions in all treated mice in relevant HGBCL or aggressive CDX models, such as SU-DHL-6 (EZH2-mutant), OCI-Ly1 (BCL2-positive), and the activated B-cell (ABC)-like OCI-Ly10 (MYD88-mutant).[3] Complete regressions were reported in 10 out of 10 mice for combinations with tazemetostat, venetoclax, and acalabrutinib, respectively.[9]

Mechanistic studies in the EZH2-mutant SU-DHL-6 model provided further insights: the combination of ARV-393 with tazemetostat resulted in more significant reductions in MYC, EZH2, and BCL2 protein levels, along with more profound BCL6 degradation, compared to ARV-393 monotherapy.[9] This suggests that simultaneously targeting multiple oncogenic pathways can lead to a more comprehensive and potent anti-tumor effect.

D. Table: Summary of Key Preclinical Combination Studies of ARV-393

Model Type (Lymphoma Subtype)	Combination Agent(s)	Key Outcome(s)	Snippet Source(s)
Aggressive DLBCL/HGBCL models	R-CHOP	Significantly greater TGI vs. R-CHOP or ARV-393 alone; Complete tumor regressions in all treated mice.	3
SU-DHL-4 CDX (HGBCL with MYC, BCL2, BCL6 rearrangements)	Rituximab (anti-CD20)	Superior TGI vs. monotherapy; Complete tumor regressions in 9/9 mice. ARV-393 increased CD20 expression.	3
SU-DHL-4 CDX (HGBCL)	Tafasitamab (anti-CD19)	Superior TGI vs. monotherapy; Complete tumor regressions in 10/10 mice (superior to tafasitamab + lenalidomide).	9
SU-DHL-4 CDX (HGBCL)	Polatuzumab vedotin (anti-CD79b ADC)	Superior TGI vs. monotherapy; Complete tumor regressions in 4/10 mice.	9
OCI-Ly10 CDX (ABC-like DLBCL, MYD88mut)	Acalabrutinib (BTK inhibitor)	Superior TGI vs. monotherapy; Tumor regressions in 10/10 mice.	3
OCI-Ly1 CDX (BCL2+)	Venetoclax (BCL2 inhibitor)	Superior TGI vs. monotherapy; Tumor regressions in 10/10 mice.	3
SU-DHL-6 CDX (HGBCL, EZH2mut)	Tazemetostat (EZH2 inhibitor)	Superior TGI vs. monotherapy; Tumor regressions in 10/10 mice. Enhanced reduction of MYC, EZH2, BCL2 proteins and greater BCL6 degradation with combination vs. ARV-393 alone.	3
>10 NHL PDX models (various BCL6-expressing lymphomas)	ARV-393 monotherapy (oral, daily for 21 days)	Anti-tumor responses ranging from total tumor regressions to partial tumor growth inhibition.	13
SU-DHL-4 CDX (HGBCL triple-hit)	ARV-393 monotherapy	Dose-responsive TGI correlated with BCL6 degradation.	1

The consistent observation of complete tumor regressions across multiple aggressive lymphoma models when ARV-393 is combined with diverse SOC agents (R-CHOP, biologics, SMIs) is a particularly compelling preclinical finding.[3] This high level of activity suggests that ARV-393 is not merely additive but exerts strong synergistic effects. Such synergy may arise from BCL6 degradation sensitizing lymphoma cells to the cytotoxic or targeted effects of partner drugs, or by simultaneously dismantling multiple oncogenic survival pathways. This robust preclinical synergy offers the potential to overcome intrinsic or acquired resistance to single-agent therapies, a major challenge in lymphoma treatment.

Furthermore, the mechanistic discovery that ARV-393 can upregulate CD20 expression on lymphoma cells is of considerable clinical interest.[3] CD20 is the target for rituximab and other anti-CD20 monoclonal antibodies, which are mainstays of B-cell lymphoma therapy. However, downregulation or loss of CD20 expression is a recognized mechanism of resistance to these agents. By restoring or increasing CD20 levels, ARV-393 could potentially enhance the efficacy of anti-CD20 therapies in tumors that are sensitive, re-sensitize tumors that have become resistant, or even extend the utility of anti-CD20 agents to patient populations with inherently low baseline CD20 expression. The proposed molecular basis for this effect, involving the de-repression of CD20 transcription via BCL6 degradation and restoration of CREBBP/EP300 activity [9], provides a plausible biological rationale.

Collectively, the extensive and positive preclinical data package, especially the compelling results from combination studies, furnishes a strong scientific basis for advancing ARV-393 into clinical trials. These findings suggest that ARV-393 could become a valuable component of future NHL treatment regimens, potentially enabling more effective chemo-free or all-oral combination strategies.[17] This could lead to accelerated clinical development, with an emphasis on evaluating combination therapies relatively early, once monotherapy safety and the recommended Phase 2 dose (RP2D) are established.

IV. Clinical Development: The ARV-393-101 Phase 1 Study (NCT06393738)

A. Study Design and Governance

The first-in-human (FIH) clinical trial evaluating ARV-393 is officially titled "A Study of ARV-393 in Relapsed/Refractory Non-Hodgkin Lymphoma".[11] It is registered on ClinicalTrials.gov under the identifier NCT06393738 [1] and also carries the secondary ID NCI-2024-06932 and the primary protocol code ARV-393-101.[15] The study is sponsored by Arvinas Inc..[11]

This is a Phase 1, open-label, multicenter, dose-escalation study.[1] The open-label design means that both investigators and participants are aware that ARV-393 is being administered. The multicenter nature of the trial facilitates patient recruitment and allows for broader experience with the investigational agent. The U.S. Food and Drug Administration (FDA) has granted "Safe to Proceed" status for the initiation of this Phase 1 trial, indicating regulatory review and acceptance of the preclinical data package supporting human testing.[13]

B. Study Objectives

The primary objectives of the ARV-393-101 study are centered on safety and dose determination:

1. To evaluate the safety and tolerability profile of ARV-393 when administered as a single agent to patients with r/r NHL.[1] This involves comprehensive monitoring and grading of adverse events.
2. To determine the Maximum Tolerated Dose (MTD) of ARV-393, if an MTD is reached during dose escalation.[1] The MTD is the highest dose that does not cause unacceptable dose-limiting toxicities.
3. To identify the Recommended Phase 2 Dose(s) (RP2D) and the optimal dosing schedule for ARV-393 to be used in subsequent clinical studies.[1]

Secondary objectives aim to gather preliminary information on the drug's behavior and efficacy:

1. To characterize the pharmacokinetic (PK) profile of ARV-393 in this patient population, assessing parameters such as absorption, distribution, metabolism, and excretion.[1]
2. To evaluate the preliminary anti-tumor activity of ARV-393, typically by assessing objective response rates according to standard lymphoma response criteria.[1]
3. To assess pharmacodynamic (PD) markers, which may include the measurement of BCL6 protein levels in tumor biopsies (if performed) or peripheral blood, to confirm target engagement and degradation in humans.[1]

C. Target Patient Population and Eligibility Criteria

The study aims to enroll approximately 112 adult participants.[15]

Key Inclusion Criteria:

• Participants must be aged ≥18 years.[15]
• Patients must have a histologically confirmed diagnosis of either:
• Relapsed or refractory mature B-cell non-Hodgkin lymphoma (NHL) for which standard curative therapies are not available or are no longer effective. These patients must have received at least two prior lines of systemic therapy.[1]
• Histologically confirmed nodal T-follicular helper cell lymphoma, angioimmunoblastic-type (nTFHL-AI, also referred to as AITL), that has recurred or progressed following institutional standard-of-care therapy.[1]
• Presence of at least one measurable lesion at study entry, as defined by appropriate lymphoma response criteria.[1]
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, indicating that patients are fully ambulatory and capable of at least light work.[1]
• Availability of freshly biopsied tumor tissue or archival tumor tissue for correlative biomarker studies.[1]
• Adequate organ function, including hematologic, renal, and hepatic parameters, as defined by specific laboratory values in the protocol.[1]
• Participants must agree to use effective methods of contraception as per study guidelines.[15]

Key Exclusion Criteria:

• Prior allogeneic stem cell transplantation (SCT) or any prior solid organ transplantation.[15]
• Autologous SCT performed ≤100 days prior to the first dose of ARV-393.[1]
• Previous CAR T-cell therapy administered ≤60 days prior to ARV-393 initiation.[1]
• Radiotherapy completed ≤2 weeks prior to ARV-393.[15]
• Systemic anticancer treatment (including chemotherapy, immunotherapy, or investigational agents) administered ≤5 half-lives or 4 weeks (whichever is shorter) prior to the first dose of ARV-393.[15]
• Known active central nervous system (CNS) involvement by lymphoma.[1]
• Presence of significant acute or chronic medical conditions that, in the investigator's judgment, would place the participant at unacceptable risk. This includes conditions such as hypereosinophilic syndrome, active interstitial lung disease or pneumonitis, or any active or uncontrolled systemic infection.[1]
• Presence of laboratory abnormalities that are deemed to place participants at unacceptable risk.[15]
• Inability to comply with protocol-specified prohibited concomitant medications or treatments.[15]

D. Intervention and Study Conduct

The investigational drug, ARV-393, is administered orally in tablet form.[1] Treatment is given in continuous 28-day cycles.[1] The study employs a Bayesian Optimal Interval (BOIN) design for dose escalation.[1] This adaptive design allows for more efficient and ethical dose finding by aiming to treat more patients at or near the optimal dose level while minimizing exposure to sub-therapeutic or overly toxic doses. ARV-393 is evaluated as a single agent (monotherapy) in this Phase 1 study.[15]

E. Current Status, Timelines, and Participating Sites

As of early May 2025, the ARV-393-101 Phase 1 study (NCT06393738) is active and recruiting participants.[15] The study officially started on September 05, 2024, and the estimated primary completion date is December 31, 2025.[15]

Participating study locations are in the United States, including sites in Connecticut (Yale University, New Haven), Michigan (Wayne State University/Karmanos Cancer Institute, Detroit), New Jersey (Rutgers Cancer Institute of New Jersey, New Brunswick), New York (Laura and Isaac Perlmutter Cancer Center at NYU Langone, New York), Ohio (Case Comprehensive Cancer Center, Cleveland), and Texas (M D Anderson Cancer Center, Houston).[19]

F. Reported Clinical Data and Presentations (as of May 2025)

As of May 2025, specific clinical results (safety, PK/PD, or efficacy data) from the ongoing ARV-393-101 Phase 1 trial have not yet been publicly presented or published in detail. Phase 1 trials, particularly in the dose-escalation phase, typically require sufficient patient enrollment and follow-up before mature data can be shared.

However, Arvinas has continued to present updated preclinical data supporting the ARV-393 program. For instance, at the American Association for Cancer Research (AACR) Annual Meeting in April 2025, Arvinas shared new preclinical combination data for ARV-393, highlighting its synergistic antitumor activity with SOC chemotherapy, biologics, and SMIs in DLBCL models.[3] These presentations reinforce the rationale for the ongoing Phase 1 monotherapy trial and lay the groundwork for future combination studies.

An abstract (P1256) presented at the European Hematology Association (EHA) 2024 Congress detailed the preclinical monotherapy efficacy of oral ARV-393 in B-cell lymphoma CDX and PDX models, noting potent BCL6 degradation and anti-tumor activity, and mentioned that the Phase 1 trial was planned to open in 2024.[13]

Investors and the scientific community anticipate initial clinical data readouts from the ARV-393-101 trial as enrollment progresses and patients are followed for safety and preliminary efficacy. Such data would typically be presented at major oncology conferences (e.g., ASCO, ASH, EHA) or through company press releases once mature enough for disclosure. The first quarter 2025 financial results and corporate update from Arvinas confirmed continued patient recruitment in the Phase 1 trial and reiterated the promising preclinical combination data.[17]

G. Second and Third-Order Insights from Clinical Development Plan:

The design of the Phase 1 trial (NCT06393738), particularly its inclusion criteria and dose escalation strategy, reflects a standard yet careful approach to FIH oncology drug development. The use of a BOIN design [1] is a modern statistical approach that aims to optimize the dose-finding process, potentially identifying the RP2D more efficiently and with greater precision than traditional 3+3 designs. This can lead to faster progression to Phase 2 studies if early signals are positive.

The patient population targeted—heavily pre-treated r/r NHL, including aggressive subtypes like nTFHL-AI [1]—represents a high unmet medical need. Positive signals in this challenging population would be particularly meaningful. The requirement for available tumor tissue [1] underscores the commitment to translational research, allowing for the correlation of clinical outcomes with BCL6 degradation levels in patient samples and other potential biomarkers. This is crucial for validating the mechanism of action in humans and identifying patient subgroups most likely to benefit.

The robust preclinical data showing synergy with a wide array of existing lymphoma therapies (R-CHOP, rituximab, tafasitamab, polatuzumab vedotin, acalabrutinib, venetoclax, tazemetostat) [3] strongly suggests that the clinical development pathway for ARV-393 will likely involve combination strategies relatively early. While the current Phase 1 study focuses on monotherapy to establish safety and single-agent activity, the preclinical evidence provides a compelling rationale to rapidly explore ARV-393 in combination regimens in subsequent Phase 1b/2 trials. This could significantly accelerate its potential integration into standard lymphoma treatment paradigms if proven effective. The potential for chemo-free or all-oral combinations [17] is particularly attractive from a patient quality-of-life perspective and could address unmet needs in populations intolerant to or relapsing after intensive chemotherapy.

V. Pharmacokinetics, Pharmacodynamics, and Molecular Properties

A. Pharmacokinetics (PK)

Detailed human pharmacokinetic data for ARV-393 are currently being generated as part of the ongoing Phase 1 clinical trial (NCT06393738).[1] One of the secondary objectives of this trial is to characterize the PK profile of ARV-393, which will include assessments of its absorption, distribution, metabolism, and excretion (ADME) following oral administration in patients with r/r NHL.

Preclinical information indicates that ARV-393 is designed to be orally bioavailable.[1] The efficacy observed in PDX models with daily oral dosing further supports its absorption and systemic exposure via the oral route in animal models.[13] The specific parameters such as half-life, Cmax​, Tmax​, and AUC in humans will be determined from the Phase 1 study.

B. Pharmacodynamics (PD)

Pharmacodynamic assessments are also a key component of the Phase 1 trial.[1] The primary PD effect of interest is the degradation of the BCL6 protein in target tissues (lymphoma cells). Preclinical studies have demonstrated a correlation between ARV-393 dose, BCL6 degradation, and anti-tumor activity.[1] In the clinical setting, PD may be assessed through analysis of tumor biopsies (if ethically and practically feasible) to measure BCL6 protein levels before and after treatment. Peripheral blood biomarkers, if identified, could also serve as surrogate markers of target engagement or downstream pathway modulation. The iterative, catalytic activity of PROTACs like ARV-393 [9] suggests that even transient exposure might lead to sustained BCL6 degradation, a hypothesis that will be explored through clinical PD assessments.

C. Molecular Properties and Formulation

ARV-393 is a small-molecule PROTAC.[1] It is a bifunctional molecule consisting of a BCL6-binding domain, a linker, and a cereblon E3 ubiquitin ligase-binding domain (derived from lenalidomide).[1] The specific chemical structure of ARV-393, including the (1r,3r) configuration around the cyclobutoxy group, has been indicated in patent literature (WO2022221673A1).[4] Calculated molecular properties from database entries include a molecular weight of approximately 898.42 g/mol, 16 hydrogen bond acceptors, 3 hydrogen bond donors, 13 rotatable bonds, a topological polar surface area of 177.58 Ų, and an XLogP of 1.33.[4] These properties are consistent with those of an orally bioavailable drug candidate. ARV-393 is administered as an oral tablet in the clinical trial.[15]

D. Regulatory Designations

As of May 2025, the provided research snippets do not explicitly state that ARV-393 has received specific regulatory designations such as Fast Track or Orphan Drug status from the FDA or EMA.[12] However, Arvinas has received Fast Track designation for another of its PROTAC degraders, vepdegestrant (ARV-471) [23], indicating the company's familiarity with these regulatory pathways. Given the unmet need in relapsed/refractory NHL, particularly for aggressive subtypes, ARV-393 could potentially qualify for such designations as clinical data emerge.

VI. Conclusion

ARV-393 is an orally bioavailable PROTAC degrader that targets the BCL6 transcriptional repressor, a key oncogenic driver in various non-Hodgkin lymphomas. Its mechanism of action, involving the recruitment of the cereblon E3 ligase to induce proteasomal degradation of BCL6, represents a novel therapeutic strategy for malignancies where BCL6 is dysregulated. This approach aims to overcome the limitations of traditional inhibitors by eliminating the entire target protein, thereby abrogating all its oncogenic functions.

Preclinical studies have demonstrated potent single-agent anti-tumor activity of ARV-393 in vitro and in vivo, including in aggressive lymphoma models and patient-derived xenografts. More strikingly, ARV-393 has shown profound synergistic effects when combined with standard-of-care chemotherapies (R-CHOP), biologics (anti-CD20, anti-CD19, anti-CD79b agents), and various small molecule inhibitors (targeting BTK, BCL2, EZH2). These combinations have frequently resulted in complete tumor regressions in preclinical settings, providing a strong rationale for their clinical investigation. The ability of ARV-393 to upregulate CD20 expression further supports its potential to enhance the efficacy of widely used anti-CD20 therapies.

The ongoing multicenter, first-in-human, Phase 1 dose-escalation study (NCT06393738) is currently evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary anti-tumor activity of ARV-393 monotherapy in patients with relapsed or refractory NHL, including DLBCL and nTFHL-AI. The determination of the MTD and RP2D from this trial will be crucial for guiding future development, particularly the design of anticipated Phase 1b/2 combination studies.

The development of ARV-393 addresses a significant unmet medical need for patients with aggressive and difficult-to-treat lymphomas. If the promising preclinical profile, especially the robust combination synergies, translates into clinical efficacy with a manageable safety profile, ARV-393 could emerge as a valuable new therapeutic option. Its unique mechanism of degrading a historically "undruggable" oncoprotein holds the potential not only to benefit patients directly but also to further validate the broader applicability of the PROTAC platform in oncology. Future clinical data readouts are eagerly awaited by the scientific and medical communities.

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