SYN-818: An Investigational DNA Polymerase Theta (Polθ) Inhibitor for Precision Oncology

I. Introduction to SYN-818

A. Overview of SYN-818

SYN-818 is an orally available, investigational novel small molecule inhibitor specifically designed to target DNA Polymerase Theta (Polθ).[1] Its development is centered on the principles of precision oncology, aiming to exploit vulnerabilities within the DNA damage repair (DDR) mechanisms of cancer cells.[1] A core concept underpinning its therapeutic strategy is synthetic lethality, particularly in tumors characterized by deficiencies in homologous recombination (HR) repair pathways, such as those with BRCA1 or BRCA2 mutations.[1]

B. Developer: SynRx Therapeutics

SYN-818 is an asset independently developed by SynRx Therapeutics Co., Ltd..[1] Founded in 2021 and headquartered in Hangzhou, China, SynRx Therapeutics is a biopharmaceutical company specializing in precision oncology, with a particular focus on DDR pathways and synthetic lethality.[1] The company successfully secured $14.2 million in seed funding to support its research and development endeavors.[6] SYN-818 represents a significant milestone for the company, being its first internally developed innovative drug candidate to progress into the clinical development stage.[1]

The advancement of SYN-818 to clinical trials, marked by Investigational New Drug (IND) application clearances in both the United States and China by mid-2024, underscores a notably rapid early development trajectory for SynRx Therapeutics. For a company established in 2021, achieving these critical regulatory milestones in two major global pharmaceutical markets within approximately three years suggests a highly efficient research and development pipeline. This rapid progression from discovery to clinical evaluation for a novel therapeutic agent is noteworthy, as preclinical development timelines in the biopharmaceutical industry often extend over longer periods. This achievement points to a robust preclinical data package for SYN-818 and an effective regulatory strategy implemented by the company.

C. Therapeutic Class and Novelty

SYN-818 is distinguished as a first-in-human DNA Polymerase Theta (POLQ) inhibitor.[2] Inhibitors of Polθ constitute an emerging and novel class of targeted therapies in oncology. The Polθ enzyme itself is frequently overexpressed in various cancer cell types, particularly those with existing DNA repair deficiencies, while its expression levels in normal, healthy tissues are typically low.[7] This differential expression profile presents a potential therapeutic window, allowing for targeted inhibition of cancer cells while minimizing effects on normal cells.

The development of Polθ inhibitors, including SYN-818, is propelled by the pressing need for innovative therapeutic strategies in oncology. These agents are particularly relevant for cancers that have developed resistance to existing treatments, such as PARP inhibitors, or for tumors harboring specific genetic vulnerabilities like HRD.[1] The therapeutic approach of targeting Polθ aims to address significant unmet medical needs by offering new options for patients with difficult-to-treat malignancies.

Table 1: SYN-818 Key Drug Information

Feature	Detail
Drug Name	SYN-818
Developer	SynRx Therapeutics Co., Ltd.
Therapeutic Class	Small molecule, DNA Polymerase Theta (Polθ) inhibitor
Target	DNA Polymerase Theta (Polθ)
Primary Mechanism of Action	Inhibition of Microhomology-Mediated End-Joining (MMEJ) and ssDNA gap filling; Synthetic lethality in Homologous Recombination Deficient (HRD) contexts

II. Mechanism of Action

A. The Role of DNA Polymerase Theta (Polθ) in DNA Repair

DNA Polymerase Theta (Polθ) is an enzyme that plays a critical role in maintaining genomic integrity, particularly through its involvement in specific DNA repair pathways. It is a key component of the Microhomology-Mediated End-Joining (MMEJ) pathway, which serves as an alternative mechanism for repairing DNA double-strand breaks (DSBs).[2] The MMEJ pathway becomes particularly significant for cell survival when the primary DSB repair pathway, homologous recombination (HR), is deficient or impaired, a common characteristic of certain cancer types.[1]

Beyond its function in MMEJ, Polθ also contributes to the repair of single-stranded DNA (ssDNA) gaps that can occur during DNA replication or as a result of DNA damage.[2] In cellular contexts where key proteins involved in HR-mediated ssDNA gap handling (such as BRCA1, BRCA2, or RAD51) are mutated or non-functional, cells may increasingly rely on Polθ, along with PARP1-mediated PARylation, for the filling of these ssDNA gaps to prevent replication fork collapse and genomic instability.[2]

B. SYN-818: A Selective and Potent Polθ Inhibitor

SYN-818 is an orally administered small molecule specifically engineered to be a selective and potent inhibitor of the enzymatic activity of Polθ.[1] By targeting Polθ, SYN-818 effectively disrupts the MMEJ repair pathway, thereby compromising a critical DNA repair mechanism in cancer cells.[1] This inhibition leads to an accumulation of unrepaired DNA damage, which can be particularly detrimental to tumor cells that are heavily reliant on Polθ for their survival and proliferation, especially those with underlying HRD.[1]

C. The Principle of Synthetic Lethality

The core therapeutic rationale for SYN-818 is founded on the principle of synthetic lethality. This biological concept describes a situation where a defect in a single gene or pathway has minimal impact on cell viability, but the simultaneous disruption of two specific genes or pathways results in cell death. In the context of SYN-818, synthetic lethality is achieved by inhibiting Polθ in cancer cells that already possess defects in other DNA repair pathways, most notably the HR pathway (e.g., due to mutations in BRCA1 or BRCA2 genes).[1] The combined loss of function in both HR and Polθ-mediated MMEJ pathways leads to an overwhelming accumulation of DNA damage, ultimately triggering selective apoptosis and death of the tumor cells.

This mechanism of action positions SYN-818 as a precision oncology agent. Its efficacy is anticipated to be most pronounced in tumors characterized by pre-existing DNA repair deficiencies, particularly HRD. This allows for a targeted therapeutic approach based on the specific genetic makeup of a patient's tumor. The requirement for BRCA mutation or other HR pathway deficiency testing by next-generation sequencing (NGS) as part of the eligibility criteria for the Phase I clinical trial of SYN-818 further underscores this precision strategy.[9] In contrast, normal, healthy cells typically possess intact HR pathways and are therefore less dependent on Polθ for DNA repair and survival. Consequently, these normal cells are expected to be less sensitive to the effects of SYN-818, providing a therapeutic window that allows for selective targeting of cancer cells while minimizing toxicity to healthy tissues.[7]

D. Potential to Overcome PARP Inhibitor Resistance

Poly(ADP-ribose) polymerase (PARP) inhibitors are an established class of drugs that have shown significant efficacy in treating HRD cancers, particularly those with BRCA mutations. However, the development of resistance to PARP inhibitors is a common clinical challenge. While not explicitly detailed for SYN-818 in the provided information, the broader scientific literature on Polθ inhibitors indicates their potential utility in tumors that have acquired resistance to PARP inhibitors.[7] Often, mechanisms of PARP inhibitor resistance still leave cancer cells dependent on alternative repair pathways like MMEJ, which is mediated by Polθ.

The observed strong preclinical synergy between SYN-818 and PARP inhibitors further supports its potential role in contexts where PARP inhibitors are employed or where resistance has emerged.[1] This synergy suggests that SYN-818 could be a valuable therapeutic option for patients whose tumors have progressed on PARP inhibitor therapy. The planned Phase Ib/II clinical trial designed to evaluate SYN-818 in combination with a PARP inhibitor directly addresses this potential application.[2] Such a combination could offer a novel strategy to enhance treatment efficacy or overcome acquired resistance, addressing a growing unmet need in the management of HRD cancers.

III. Preclinical Development

The advancement of SYN-818 into clinical trials was predicated on a robust preclinical data package demonstrating its potential as a targeted anti-cancer agent. These studies evaluated its efficacy, pharmacokinetic properties, and safety profile.

A. Summary of Key Preclinical Findings

Efficacy (Monotherapy):

Preclinical investigations consistently showed that SYN-818 possesses excellent efficacy when used as a standalone agent, particularly in cellular and animal models representing HRD tumors.2 A striking demonstration of its potency and selectivity was observed in DLD1 cancer cells; SYN-818 exhibited over 8000-fold greater selectivity in killing BRCA2 knockout (KO) cells compared to their BRCA2 wild-type (parental) counterparts.3 This significant differential cytotoxicity underscores the potent synthetic lethal interaction between Polθ inhibition by SYN-818 and BRCA2 deficiency.

Efficacy (Combination Therapy):

The therapeutic potential of SYN-818 appears to be further enhanced when used in combination with other DNA-damaging or DDR-targeting agents. Preclinical studies, conducted both in vitro and in vivo, revealed remarkable and robust synergistic anti-tumor effects when SYN-818 was combined with PARP inhibitors.1 This synergy is mechanistically plausible, given the distinct but complementary roles of PARP and Polθ in DNA repair, particularly in HRD settings. Beyond PARP inhibitors, preclinical data also indicated strong synergistic interactions between SYN-818 and conventional chemotherapy agents, as well as with topoisomerase I (TOPi)-based antibody-drug conjugates (ADCs).3 These findings suggest a broad applicability for SYN-818 in various combination regimens.

Pharmacokinetics (PK):

Pharmacokinetic assessments in preclinical models indicated that SYN-818 possesses an acceptable and favorable PK profile.2 These characteristics are crucial for achieving adequate drug exposure at the tumor site while maintaining manageable systemic concentrations.

Safety and Tolerability:

The preclinical safety evaluation of SYN-818 pointed towards a favorable safety profile.2 Importantly, the compound demonstrated a low risk for inhibiting cytochrome P450 (CYP450) enzymes and a low potential for time-dependent inhibition (TDI) of these enzymes.3 This suggests a reduced likelihood of clinically significant drug-drug interactions when SYN-818 is co-administered with other medications metabolized by CYP450 pathways. Furthermore, dedicated safety studies indicated a low risk of QT interval prolongation, a critical cardiovascular safety parameter.3 Comprehensive assessments in preclinical models did not reveal any significant adverse impacts on the central nervous system (CNS), respiratory system, or cardiovascular system.3

B. "Best-in-Class" Potential

Based on the compelling preclinical data package, SynRx Therapeutics has positioned SYN-818 as a candidate with the potential to be a "best-in-class" Polθ inhibitor.[1] This assertion is supported by several key preclinical attributes: high selectivity for killing cancer cells with specific DNA repair defects (e.g., >8000-fold selectivity in BRCA2 KO cells), potent monotherapy and combination efficacy, and a favorable safety profile, including a low propensity for drug-drug interactions and no major organ system toxicity signals in preclinical studies.[1] While these preclinical metrics are indeed impressive and provide a strong foundation for this claim, the definitive establishment of "best-in-class" status will ultimately depend on comparative clinical data against other Polθ inhibitors that are also advancing through clinical development. Such clinical comparisons are not yet available.

Table 2: Summary of Key Preclinical Findings for SYN-818

Parameter	Finding	Source Snippet(s)
Selectivity (HRD context)	>8000-fold in BRCA2 KO vs WT DLD1 cells	3
Synergy with PARP Inhibitors	Remarkable and robust in vitro and in vivo	1
Synergy with Chemo/ADCs	Strong synergy with chemotherapy and TOPi-based ADCs	3
Pharmacokinetic Profile	Acceptable and favorable	2
Safety - CYP450 Interaction	Low risk for CYP450 inhibition and Time-Dependent Inhibition (TDI)	3
Safety - QT Prolongation	Low risk	3
Safety - Organ Systems (CNS, Respiratory, Cardiovascular)	No significant impact observed	3

IV. Clinical Development Program

A. Overview of Clinical Strategy

The clinical development pathway for SYN-818 is designed to systematically evaluate its safety, tolerability, pharmacokinetics, and anti-tumor activity. The initial phase focuses on establishing these parameters for SYN-818 as a monotherapy in patients with advanced solid tumors. Following the monotherapy assessment, the strategy incorporates the evaluation of SYN-818 in combination therapy regimens, with a particular emphasis on its use with PARP inhibitors in genetically defined patient populations, specifically those with HRD, including BRCA mutations.[2] This staged approach allows for a thorough understanding of the drug's profile before exploring its potential in more targeted and potentially synergistic combinations.

B. Phase I Monotherapy Study (NCT06666270 / CTR20244063; SYN-818-101)

The cornerstone of the early clinical development of SYN-818 is a first-in-human, Phase I study.

Table 3: Overview of Clinical Trial NCT06666270 (SYN-818-101)

Parameter	Detail
Trial ID(s)	NCT06666270 (ClinicalTrials.gov), CTR20244063 (China), SYN-818-101 (Study ID)
Phase	Phase I
Title	A First-in-human, Phase I Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Preliminary Anti-tumor Activity of SYN818, a DNA Polymerase Theta (POLQ) Inhibitor Alone in Patients with Locally Advanced or Metastatic Solid Tumors
Sponsor	Hangzhou SynRx Therapeutics Biomedical Technology Co., Ltd.
Collaborators	Fudan University Shanghai Cancer Center, Shanghai, China; Henan Breast Cancer Centre, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China 2
Design	Open-label, multicenter, dose-escalation study
Primary Purpose	Treatment
Intervention	SYN-818 monotherapy (oral administration)
Key Objectives	Primary: Safety, tolerability, Maximum Tolerated Dose (MTD)/Recommended Phase 2 Dose (RP2D). Secondary: Pharmacokinetics (PK), preliminary anti-tumor efficacy (ORR, survival metrics).
Current Status (Apr 2025)	Enrolling
Estimated Enrollment (Dose Escalation)	~30 patients

Study Design:

This Phase I trial is an open-label, multicenter, dose-escalation investigation of SYN-818 administered as a monotherapy.2 The study is actively being conducted at clinical sites in China, including Fudan University Shanghai Cancer Center and Henan Breast Cancer Centre.2

Objectives:

The primary objectives are to thoroughly assess the safety and tolerability profile of SYN-818 across escalating dose levels and to determine the MTD and/or the RP2D for subsequent studies.2 Secondary objectives include characterizing the single and multiple-dose PK of SYN-818, and obtaining preliminary signals of anti-tumor activity, measured by parameters such as Objective Response Rate (ORR) and other survival metrics.2

Target Patient Population:

The study enrolls adult patients (aged ≥18 years) who have histologically or cytologically confirmed locally advanced or metastatic solid tumors.2 Eligible patients must have experienced disease progression following, or be intolerant to, available standard-of-care therapies, indicating an advanced-stage population with limited treatment options. While the study is open to various solid tumors, specific tumor types mentioned as being of interest include breast cancer, ovarian cancer, and prostate cancer.9 A key aspect of patient selection is the mandatory provision of tumor tissue samples (fresh, frozen, or archival paraffin-embedded) or peripheral blood samples for the detection of BRCA mutations or other deficiencies in the HR pathway, typically assessed by NGS.9

Key Eligibility Criteria:

The selection of patients for this first-in-human study is governed by stringent inclusion and exclusion criteria to ensure patient safety and the interpretability of study results.

Table 4: Key Eligibility Criteria for NCT06666270 (SYN-818-101)

Inclusion Criteria	Exclusion Criteria
Age ≥18 years 2	Previous or current use of POLQ inhibitors 2
Histologically/cytologically confirmed locally advanced or metastatic solid tumors, progressed on/intolerant to SOC 2	Known hypersensitivity to SYN-818 or its excipients 9
ECOG Performance Status 0-1 2	Symptomatic or uncontrolled CNS/meningeal metastasis 2
Life expectancy ≥3 months (or ≥12 weeks) 2	Other active malignancy within 5 years prior (exceptions for certain cured localized cancers) 9
At least one measurable lesion per RECIST v1.1 2	Myelodysplastic syndrome (MDS)/Acute myeloid leukemia (AML) or features suggestive of MDS/AML 9
Adequate organ and bone marrow function 2	Dysphagia, refractory nausea/vomiting, malabsorption syndromes affecting drug absorption 9
Willingness to provide tumor tissue/blood for HRD testing 9	Major surgery or serious trauma within 4 weeks prior to first dose, or unresolved AEs from surgery 9
	Use of prohibited potent CYP3A4/BCRP/P-gp inhibitors or inducers within 2 weeks prior to first dose or during study 9
	Unresolved TEAEs from prior treatment (not resolved to ≤ Grade 1 or baseline) 2

Current Status, Timeline, and Enrollment:

Information regarding the trial's status has evolved. Initial registry entries (e.g., on ClinicalTrials.gov) around late 2024 indicated a "Not Yet Recruiting" status with an anticipated start date of November 30, 2024, and an estimated study completion date of December 30, 2026.9 However, more current information, particularly from presentations at the American Association for Cancer Research (AACR) Annual Meeting in April 2025 (Abstract CT152), confirms that the study (SYN-818-101) is indeed active and enrolling patients.2 This discrepancy highlights the dynamic nature of clinical trial information and the value of recent conference disclosures for the most up-to-date status.

As of February 12, 2025, data presented indicated that four patients with solid tumors had been enrolled and received SYN-818 across the first two dose levels (50 mg once daily, n=1; 100 mg once daily, n=3).[2] By a later data cut-off of April 2, 2025, a total of seven patients had been enrolled across the first three dose-escalation cohorts, which included doses of 50 mg, 100 mg, and 200 mg administered once daily.[3] The dose escalation phase employs a Bayesian Optimal Interval (BOI) design, a statistical method often used in early-phase trials to guide dose adjustments based on observed toxicities. The estimated total enrollment for this dose-escalation portion of the study is approximately 30 patients.[2]

Preliminary Phase I Results (from AACR 2025 Poster CT152):

Early data from the initial cohorts of the Phase I monotherapy study were presented at the AACR 2025 Annual Meeting, providing the first insights into the clinical behavior of SYN-818 in humans.2 These preliminary findings are critical for assessing the drug's potential and guiding further development.

Table 5: Preliminary Safety and PK from Phase I (NCT06666270) - AACR 2025 Data

Data Category	Reported Finding (as of April 2, 2025, for 7 patients across 50mg, 100mg, 200mg QD cohorts)	Source Snippet(s)
Dose-Limiting Toxicities (DLTs)	None observed	2
Grade ≥3 Related TEAEs	None reported	2
Common Adverse Events (AEs)	Most common AEs were Grade 1; Grade 1 nausea and fatigue reported in earlier data cut (2/4 and 3/4 patients respectively for 50mg & 100mg cohorts)	2
PK - Exposure	Plasma exposure increased dose-proportionally from 50 mg to 200 mg once daily; exceeded expectations from preclinical studies.	3
PK - Target Coverage	Initial PK profiles at dose levels 1 to 3 demonstrated robust target coverage.	2

The initial safety data from the first few cohorts are encouraging. SYN-818 monotherapy has been well-tolerated at the doses tested so far, with no DLTs reported.[2] Furthermore, no drug-related TEAEs of Grade 3 or 4 severity were observed.[2] The most frequently reported AEs were mild (Grade 1), with nausea and fatigue being noted.[2] This early safety profile is a positive indicator for continued dose escalation and development.

The pharmacokinetic profile of SYN-818 in humans has also been favorable. Systemic exposure to SYN-818 increased in a dose-proportional manner across the 50 mg to 200 mg once-daily dose levels.[3] Notably, the observed human PK profiles were consistent with, and in some cases exceeded, preclinical predictions, suggesting more favorable drug exposure than initially anticipated.[2] The initial PK data from the first three dose levels indicate robust target coverage, which is essential for achieving the desired pharmacological effect.[2] These positive early clinical signals for both safety and PK provide a critical initial validation for this novel agent and support continued investigation.

The preliminary anti-tumor efficacy of SYN-818 is a secondary endpoint in this Phase I study.[2] While the primary focus of these early cohorts is on safety and PK, any observed signs of anti-tumor activity would be highly encouraging. Specific efficacy data, such as ORR, from these initial cohorts were not detailed in the provided materials beyond its inclusion as an endpoint.

C. Planned Phase Ib/II Combination Study

Building on the monotherapy data and the strong preclinical rationale for combination therapy, SynRx Therapeutics has outlined plans for a subsequent Phase Ib/II trial.

Rationale:

The decision to evaluate SYN-818 in combination with PARP inhibitors is strongly supported by preclinical studies demonstrating significant synergy between these two classes of agents.1 Mechanistically, inhibiting both Polθ (involved in MMEJ and ssDNA gap filling) and PARP (involved in base excision repair and ssDNA break repair, and whose inhibition is synthetically lethal with HRD) is expected to create an overwhelming burden of unrepaired DNA damage in HRD cancer cells, leading to enhanced tumor cell killing.

Study Design and Target Population:

A Phase Ib/II trial is planned to assess the safety and efficacy of SYN-818 administered in combination with a PARP inhibitor.2 This study will specifically enroll patients with locally advanced or metastatic solid tumors that harbor BRCA mutations or other documented HRR mutations.2 This genetically defined patient population is most likely to benefit from the synthetic lethal interaction targeted by this combination.

Anticipated Timeline and Objectives:

The Phase Ib portion of this combination study is anticipated to commence in the second half of 2025.3 The primary objectives of the Phase Ib component will likely focus on evaluating the safety and tolerability of the combination regimen, identifying any new or exacerbated toxicities, and determining the RP2D for the combination of SYN-818 and the PARP inhibitor.3 Preliminary efficacy of the combination will also be assessed. This planned trial represents a scientifically sound and strategically important step in the clinical development of SYN-818. By targeting a patient population with specific biomarkers (BRCA/HRR mutations), the study adheres to precision medicine principles, thereby increasing the probability of demonstrating clinical benefit and defining a clear path for SYN-818 in a clinically relevant setting.

V. Regulatory Status

SYN-818 has achieved key early regulatory milestones in two major global pharmaceutical markets, reflecting a coordinated approach to its global development.

A. United States Food and Drug Administration (FDA)

On July 24, 2024, SynRx Therapeutics announced that the U.S. FDA completed its safety review of the Investigational New Drug (IND) application for SYN-818 and granted clearance for clinical studies to proceed in the United States.[1] This clearance is a critical step, allowing the company to initiate human trials under U.S. regulatory oversight.

B. China National Medical Products Administration (NMPA) - Center for Drug Evaluation (CDE)

Concurrently with the U.S. milestone, the IND application for SYN-818 was accepted by the Center for Drug Evaluation (CDE) of the National Medical Products Administration (NMPA) in China on July 23, 2024.[1] This acceptance paves the way for clinical development in China. The ongoing Phase I trial (NCT06666270) is being conducted in China, indicating active clinical investigation in this region.[2]

The near-simultaneous IND clearance by the US FDA and acceptance by China's CDE in July 2024 represents a significant achievement for SynRx Therapeutics, particularly for an early-stage asset from a relatively young company. This synchronized regulatory entry into two key global markets suggests a robust and comprehensive preclinical data package that met the rigorous expectations of both regulatory authorities. It also points towards a well-executed global regulatory strategy aimed at expediting the development of SYN-818. Such parallel progression can potentially lead to faster data generation and, if the drug proves successful, quicker access for patients in multiple major regions.

C. Other Regulatory Designations

The provided research materials do not mention any other specific regulatory designations for SYN-818, such as Fast Track, Breakthrough Therapy, or Orphan Drug status, from either the FDA, EMA, or other regulatory bodies at this time.

VI. Therapeutic Indications and Potential

A. Current Investigational Indications

The initial clinical development of SYN-818 is focused on patients with locally advanced or metastatic solid tumors who have exhausted standard therapeutic options.[1] The broad eligibility in the ongoing Phase I trial allows for signal-seeking across various tumor histologies.

Based on the Phase I eligibility criteria and the drug's mechanism of action, specific solid tumors of particular interest for SYN-818 development include:

• Breast Cancer: Especially tumors with BRCA mutations or other HRD characteristics.[9]
• Ovarian Cancer: Another malignancy often associated with HRD and BRCA mutations.[9]
• Prostate Cancer: Particularly metastatic castration-resistant prostate cancer (mCRPC) with HRD.[9]

A central theme in the therapeutic targeting of SYN-818 is the presence of Homologous Recombination Deficiency (HRD). Tumors exhibiting HRD, including those with deleterious BRCA1/2 mutations, are hypothesized to be particularly sensitive to Polθ inhibition due to their increased reliance on alternative DNA repair pathways like MMEJ.[1] This forms the basis for its investigation both as a monotherapy and in combination strategies within this molecularly defined patient subgroup.

B. Potential as a "Best-in-Class" Polθ Inhibitor

SynRx Therapeutics has suggested that SYN-818 holds the potential to be a "best-in-class" Polθ inhibitor.[1] This assertion is founded on its strong preclinical profile, which includes high target selectivity, potent anti-tumor efficacy (especially in HRD models, with >8000-fold selectivity for BRCA2 KO cells), a favorable pharmacokinetic and safety profile (including low risk of CYP450 interactions and QT prolongation), and robust synergistic activity with PARP inhibitors.[1] The early clinical data from the Phase I study, showing good tolerability and a PK profile that met or exceeded preclinical expectations, provide initial support for this potential.[2] However, the landscape of Polθ inhibitors is evolving, with other agents also in development.[7] Definitive "best-in-class" status will ultimately be determined by comparative clinical trial data, which is not yet available.

C. Future Outlook and Unmet Needs

SYN-818 is being developed to address significant unmet medical needs in oncology. Its mechanism of action, targeting a fundamental DNA repair pathway (Polθ), coupled with its synthetic lethal activity in HRD tumors and its demonstrated synergy with other DDR agents, suggests a broad therapeutic horizon.

The potential applications for SYN-818 include:

• Monotherapy: For patients with HRD-positive cancer cells, where Polθ inhibition alone may be sufficient to induce tumor cell death.[1]
• Combination Therapy: In combination with PARP inhibitors, where it may enhance efficacy or overcome resistance.[1] Preclinical data also support combinations with radiotherapy and certain ADCs.[1]
• Addressing Treatment Resistance: A critical unmet need is the development of therapies for cancers that have become resistant to existing treatments, including PARP inhibitors. Polθ inhibitors like SYN-818 are being explored for their potential to be effective in such PARPi-resistant settings.[1]
• Improving Tolerability: By enabling synergistic effects, SYN-818 could potentially allow for the use of lower, less toxic doses of combination partners, thereby reducing the overall clinical toxicity of treatment regimens.[1]

The initial broad inclusion criteria for the Phase I trial, encompassing various advanced solid tumors, facilitate the identification of tumor types most sensitive to SYN-818, which will inform the design of subsequent, more focused clinical studies. The successful development of SYN-818 could offer new hope for patients who have exhausted standard therapies or who have tumors with specific genetic vulnerabilities that make them susceptible to Polθ inhibition.

VII. Summary and Conclusion

A. Recap of SYN-818's Profile

SYN-818 is an investigational, orally administered, selective small molecule inhibitor of DNA Polymerase Theta (Polθ). Developed by SynRx Therapeutics, a precision oncology company founded in 2021, SYN-818 targets a critical enzyme in the Microhomology-Mediated End-Joining (MMEJ) DNA repair pathway. Its therapeutic strategy is primarily based on the principle of synthetic lethality, aiming to selectively kill cancer cells with pre-existing defects in Homologous Recombination (HR) repair, such as those with BRCA1/2 mutations.

Preclinical studies have demonstrated a compelling profile for SYN-818, characterized by high selectivity for HR-deficient cells, potent monotherapy efficacy in relevant models, and significant synergistic anti-tumor activity when combined with PARP inhibitors, chemotherapy, and certain antibody-drug conjugates. The preclinical pharmacokinetic and safety assessments were also favorable, indicating good drug-like properties and a potentially manageable safety profile in humans.

B. Current Development Stage

SYN-818 has rapidly transitioned from preclinical research to clinical evaluation. Key regulatory milestones include the simultaneous Investigational New Drug (IND) application clearance by the U.S. Food and Drug Administration (FDA) and acceptance by China's National Medical Products Administration (NMPA) in July 2024.

Currently, a first-in-human Phase I monotherapy clinical trial (NCT06666270 / SYN-818-101) is underway in China. This open-label, dose-escalation study is evaluating the safety, tolerability, pharmacokinetics, and preliminary anti-tumor activity of SYN-818 in patients with locally advanced or metastatic solid tumors. Initial data from the first few dose cohorts, presented in early 2025, suggest that SYN-818 is well-tolerated at the doses tested, with no dose-limiting toxicities reported and a pharmacokinetic profile that meets or exceeds preclinical predictions.

Looking ahead, a Phase Ib/II clinical trial is planned to investigate SYN-818 in combination with a PARP inhibitor, specifically targeting patients with tumors harboring BRCA or other HRR mutations. This combination study is anticipated to begin in the second half of 2025.

C. Concluding Remarks on Potential in Precision Oncology

SYN-818 emerges as a promising new entrant in the field of targeted cancer therapy, particularly for malignancies characterized by specific DNA repair deficiencies. Its mechanism of action, exploiting the synthetic lethal relationship between Polθ inhibition and HRD, aligns with the paradigm of precision oncology, aiming to deliver tailored treatments based on the molecular profile of a patient's tumor.

The continued clinical development of SYN-818 will be crucial in defining its therapeutic role. Key upcoming inflection points include the determination of the Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) from the ongoing Phase I monotherapy study, further elucidation of its safety profile across a broader patient population and dose range, and initial efficacy signals from this trial. Subsequently, the initiation and early results from the planned Phase Ib/II PARP inhibitor combination study will be critical for validating its potential in a highly relevant clinical setting and for substantiating its "best-in-class" aspirations. If successful, SYN-818 could offer a valuable new therapeutic option for patients with difficult-to-treat solid tumors, potentially addressing unmet needs in overcoming treatment resistance and improving outcomes in genetically defined cancer populations.

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