HSK-41959: An Investigational MTA-Cooperative PRMT5 Inhibitor for MTAP-Deleted Solid Tumors

1. Introduction to HSK-41959

1.1. Overview of HSK-41959

HSK-41959, also referred to as HSK41959-2 in some preclinical documentation, is an orally administered investigational small molecule drug.[1] The oral route of administration is a notable feature, as it generally offers greater patient convenience and can lead to improved treatment adherence, particularly in the context of chronic cancer therapies, when compared to intravenous alternatives. In China, HSK-41959 has been classified as a Class 1 Chemical Drug by the National Medical Products Administration (NMPA).[3] This classification is significant as it denotes a new chemical entity that has not been previously marketed either in China or internationally, underscoring its innovative nature within the pharmaceutical landscape.

1.2. Developer: Haisco Pharmaceutical Group Co., Ltd.

The development of HSK-41959 is attributed to Haisco Pharmaceutical Group Co., Ltd., a Chinese pharmaceutical company.[3] Its subsidiary, Shanghai Haisishengnuo Pharmaceutical Technology Co., Ltd., is frequently cited as the originator organization.[1] Founded in 2000, Haisco Pharmaceutical Group is a publicly listed entity in China with a primary focus on the research, development, and commercialization of specialty pharmaceuticals.[4] The company's operational scope is extensive, with over 4000 employees globally and 26 subsidiary companies, reflecting a diversified interest across the healthcare industry. Haisco's research and development efforts are concentrated on small molecule chemical innovative drugs and innovative chemical generic drugs, indicating a broad capability set that spans the pharmaceutical value chain.[4] This established corporate infrastructure and commitment to innovation provide a solid foundation for the clinical advancement of HSK-41959.

1.3. Therapeutic Class and Novelty: Oral MTA-Cooperative PRMT5 Inhibitor

HSK-41959 is characterized as a potent and highly selective small molecule inhibitor of Protein Arginine Methyltransferase 5 (PRMT5).[1] Its specific mechanism of action is that of a methylthioadenosine (MTA)-cooperative PRMT5 inhibitor.[2] This distinct mode of action differentiates HSK-41959 from earlier, first-generation PRMT5 inhibitors and forms the basis of its therapeutic rationale in a precisely defined patient demographic. The primary therapeutic area for HSK-41959 is oncology. It is being developed for the treatment of patients with locally advanced or metastatic solid tumors that are characterized by a specific genetic alteration: the homozygous deletion of the Methylthioadenosine Phosphorylase (MTAP) gene.[1]

The development of HSK-41959 as an MTA-cooperative PRMT5 inhibitor specifically for MTAP-deleted cancers signals Haisco Pharmaceutical Group's strategic move into the domain of precision oncology. This approach targets a known genetic vulnerability present in a subset of cancers. MTAP gene deletion is observed in approximately 10-15% of all human cancers, leading to the intracellular accumulation of MTA.[2] This MTA accumulation creates a unique biochemical environment within the cancer cells. MTA-cooperative PRMT5 inhibitors, such as HSK-41959, are designed to exploit this specific environment, thereby achieving selective targeting of tumor cells.[2] Consequently, HSK-41959 is not intended for broad-spectrum oncological use but rather for a genetically defined patient population. This precision medicine strategy holds the potential for higher response rates in appropriately selected patients and may facilitate a more streamlined regulatory approval pathway if strong biomarker-linked efficacy can be demonstrated.

Table 1: HSK-41959 Drug Profile Summary

Feature	Details	Source(s)
Drug Name(s)	HSK-41959, HSK41959-2	1
Developer	Haisco Pharmaceutical Group Co., Ltd.	3
Originator Organization	Shanghai Haisishengnuo Pharmaceutical Technology Co., Ltd.	1
Drug Type	Oral Small Molecule	1
Target	Protein Arginine Methyltransferase 5 (PRMT5)	1
Mechanism of Action	Methylthioadenosine (MTA)-Cooperative PRMT5 inhibitor	2
Key Indication	Locally advanced or metastatic MTAP-deleted solid tumors	1
Current Development Phase (Highest)	Phase 1	1
Regulatory Classification (China)	Class 1 Chemical Drug	3

2. Mechanism of Action and Scientific Rationale

2.1. The Role of PRMT5 in Oncology

Protein Arginine Methyltransferase 5 (PRMT5) is a critical enzyme belonging to the type II class of arginine methyltransferases. Its primary function involves the symmetric dimethylation of arginine residues on a variety of protein substrates, including histones and components of the RNA splicing machinery.[2] These modifications play crucial roles in regulating numerous essential cellular processes such as gene transcription, RNA processing, DNA damage repair, and signal transduction. Given its fundamental role in cell biology, PRMT5 is essential for cell survival. Notably, PRMT5 is frequently found to be highly expressed in many types of cancer, where it broadly promotes oncogenic processes, contributing to tumor initiation, growth, and survival.[8] The essential nature of PRMT5 in both normal and cancerous cells underscores the therapeutic challenge: to achieve anti-cancer effects, its inhibition must be highly selective for cancer cells to avoid unacceptable toxicity to healthy tissues.

2.2. Synthetic Lethality in MTAP-Deleted Cancers: The MTA-PRMT5 Axis

A significant breakthrough in targeting PRMT5 for cancer therapy emerged from the understanding of its interplay with the Methylthioadenosine Phosphorylase (MTAP) gene. Homozygous deletion of the MTAP gene is a common genetic event, occurring in approximately 10-15% of all human cancers. This deletion is frequently observed in various malignancies, including non-small cell lung cancer (NSCLC), mesothelioma, pancreatic cancer, and glioblastoma.[2]

The MTAP enzyme plays a key role in the methionine salvage pathway by catalyzing the phosphorolysis of 5'-deoxy-5'-methylthioadenosine (MTA) into adenine and 5-methylthio-D-ribose-1-phosphate. The loss of MTAP function due to gene deletion leads to a significant accumulation of MTA specifically within the MTAP-deleted cancer cells.[2] This accumulated MTA acts as an endogenous, moderately potent, and selective inhibitor of PRMT5. It achieves this by competing with S-adenosyl methionine (SAM), the universal methyl donor for PRMT5, for binding to the enzyme's active site. Consequently, in MTAP-deleted cancer cells, PRMT5 activity is already partially compromised due to the high intracellular MTA concentrations.[8]

This pre-existing partial inhibition of PRMT5 in MTAP-deleted cells renders them uniquely vulnerable to further pharmacological inhibition of PRMT5. This phenomenon is a classic example of synthetic lethality, where the combination of two non-lethal genetic or molecular alterations (MTAP deletion and PRMT5 inhibition) results in cell death, while cells with only one alteration (e.g., normal cells with functional MTAP, or MTAP-deleted cells without further PRMT5 inhibition) remain viable.[8] This synthetic lethal relationship provides a therapeutic window to selectively target MTAP-deleted cancer cells.

2.3. HSK-41959: MTA-Cooperative Inhibition of PRMT5

HSK-41959 is specifically designed as an MTA-cooperative PRMT5 inhibitor.[2] This means that the drug exhibits significantly enhanced binding and inhibitory activity against PRMT5 when MTA is already bound to the enzyme. Preclinical data indicate that HSK-41959 inhibits PRMT5 with an IC50​ (half-maximal inhibitory concentration) of 0.80 nM in the presence of MTA.[2] This MTA-cooperative mechanism allows HSK-41959 to preferentially target PRMT5 in MTAP-deleted cancer cells, which have high intracellular MTA levels, while exerting minimal activity against PRMT5 in normal cells where MTA concentrations are low.[2] This targeted approach is the cornerstone of the drug's design, aiming to maximize anti-tumor efficacy while minimizing off-target effects.

2.4. Potential for Enhanced Therapeutic Index

A major challenge with first-generation PRMT5 inhibitors, which lack MTA cooperativity, has been their on-target toxicity, particularly hematologic adverse events. These toxicities arise because PRMT5 is also essential for the function of normal cells, especially rapidly dividing hematopoietic stem and progenitor cells.[2] The MTA-cooperative mechanism of HSK-41959 is hypothesized to confer a significantly better safety profile. By selectively inhibiting PRMT5 in the high-MTA environment of MTAP-deleted cancer cells, HSK-41959 is expected to spare normal cells, thereby widening the therapeutic index—the ratio between the dose that produces a therapeutic effect and the dose that causes toxicity.[2]

The development of MTA-cooperative PRMT5 inhibitors like HSK-41959 represents a rational evolution in drug design, directly addressing the dose-limiting hematologic toxicities that hampered the clinical utility of earlier, non-selective PRMT5 inhibitors.[2] The discovery of MTA's differential accumulation in MTAP-deleted cancer cells versus normal cells provided a crucial biochemical distinction that could be exploited pharmacologically.[8] MTA-cooperative inhibitors are specifically engineered to leverage this MTA accumulation, thereby aiming to overcome the primary limitation of their predecessors by achieving enhanced tumor selectivity. This selectivity is paramount for developing a viable and effective therapeutic agent targeting PRMT5.

Furthermore, the entire therapeutic strategy underpinning HSK-41959 relies on the MTAP deletion status of the tumor. This necessitates that patient selection be guided by robust biomarker testing, likely involving genomic sequencing of tumor tissue to identify MTAP gene deletions. Without MTAP deletion and the consequent MTA accumulation, HSK-41959 would likely lose its preferential target engagement in cancer cells. In such a scenario, it might behave more like a non-selective PRMT5 inhibitor, potentially leading to increased toxicity without a corresponding increase in efficacy. Therefore, the development and implementation of accurate and reliable MTAP deletion diagnostics are integral to the clinical development of HSK-41959 and its eventual application, ensuring that the drug is administered to the patient population most likely to benefit and least likely to experience undue adverse effects.

3. Preclinical Profile of HSK-41959

The preclinical evaluation of HSK-41959 has provided crucial data supporting its mechanism of action and therapeutic potential, particularly highlighting its selectivity for MTAP-deleted cancer cells and a potentially favorable safety profile.

3.1. In Vitro Potency and Selectivity

In vitro studies have been instrumental in characterizing the activity of HSK-41959. Using the HCT116 colon cancer cell line, comparisons were made between cells with a homozygous deletion of the MTAP gene (MTAP-del) and their wild-type counterparts (MTAP-WT).

• Cell Proliferation Inhibition: HSK-41959 demonstrated significant inhibition of cell proliferation in the HCT116 MTAP-del cell line, with a GI50 (concentration causing 50% growth inhibition) value of 19.89 nM.[2] This activity was markedly more potent compared to its effect on HCT116 MTAP-WT cells, resulting in an approximately 45-fold selectivity for the MTAP-deleted cells in terms of growth inhibition.[2]
• SDMA Inhibition: Symmetric dimethylarginine (SDMA) is a direct product of PRMT5 enzymatic activity, and its levels serve as a pharmacodynamic biomarker for PRMT5 inhibition. HSK-41959 showed high potency in reducing SDMA levels in the HCT116 MTAP-del cell line, with an IC50​ of 3.39 nM.[2] In stark contrast, its ability to inhibit SDMA in the HCT116 MTAP-WT cell line was substantially weaker, with an IC50​ of 499 nM. This translates to an approximately 147-fold selectivity in terms of target engagement (SDMA inhibition) in MTAP-deleted cells versus MTAP wild-type cells.[2]

These pronounced selectivity figures (45-fold for growth inhibition and 147-fold for SDMA inhibition) are critical preclinical findings. They strongly support the MTA-cooperative mechanism of HSK-41959 and suggest a potentially wide therapeutic window, where the drug could effectively target cancer cells while sparing normal cells.

3.2. Heme-Related Toxicity Assessment

Given that hematologic toxicity was a significant concern with earlier, non-selective PRMT5 inhibitors, the preclinical assessment of HSK-41959 included an evaluation of its potential impact on hematopoietic cells. An in vitro proliferation assay using CD34+ hematopoietic stem cells (HSCs) was employed for this purpose.2

HSK-41959 exhibited weak inhibition of CD34+ HSC proliferation, with an IC50​ of 544 nM.2 This was notably less potent than a first-generation PRMT5 inhibitor, which demonstrated an IC50​ of 35.39 nM in the same assay.2 The greater than 15-fold difference in IC50​ values (544 nM for HSK-41959 versus 35.39 nM for the comparator) against hematopoietic stem cells is a significant observation. It provides preclinical evidence supporting the hypothesis that HSK-41959 may possess an improved safety profile concerning the hematologic adverse events that plagued earlier PRMT5 inhibitors, a crucial factor for its clinical viability.

3.3. In Vivo Efficacy in Xenograft Models

The anti-tumor activity of HSK-41959 was further investigated in vivo using mouse xenograft models derived from HCT116 cells.

• HCT116 MTAP-del Xenograft Model:
• Oral administration of HSK-41959 once daily at a dose of 25 mg/kg resulted in a 62% tumor growth inhibition (TGI). This was accompanied by an 89% inhibition of PRMT5-dependent SDMA protein levels in the tumor tissue, indicating strong target engagement.[2]
• Increasing the daily oral dose to 100 mg/kg led to an even more pronounced anti-tumor effect, with an 88% TGI and 95% SDMA inhibition.[2]
• HCT116 MTAP-WT Xenograft Model:
• In contrast to its effects in the MTAP-del model, HSK-41959, even at the high dose of 100 mg/kg daily, did not demonstrate tumor growth inhibition in the HCT116 MTAP-WT xenograft model.[2]

These in vivo results are compelling. The dose-dependent and significant anti-tumor activity observed exclusively in the MTAP-deleted xenograft model, along with robust target engagement (SDMA inhibition), and the lack of efficacy in the MTAP wild-type model at a high dose, provide strong in vivo proof-of-concept for the MTA-cooperative mechanism of HSK-41959 and its selective anti-tumor effect.

3.4. Summary of Preclinical Pharmacokinetics and Safety

HSK-41959 is formulated for oral administration.[3] Broader preclinical research findings have indicated that HSK-41959 exhibits good tolerability and a substantial safety window.[3] While these descriptions are qualitative, they align with the quantitative data from the CD34+ HSC assay and the selective in vivo efficacy observed, collectively supporting the decision to advance HSK-41959 into clinical trials.

The consistency of the preclinical data is noteworthy. There is a strong correlation between the MTAP-deletion status, the MTA-cooperative PRMT5 inhibition by HSK-41959, and the resultant anti-tumor activity. The high in vitro selectivity observed in MTAP-del cells translates directly to selective in vivo efficacy and target engagement. Specifically, the biochemical potency of HSK-41959 for PRMT5 in the presence of MTA (IC50​ 0.80 nM) [2] underpins its potent and selective inhibition of cell growth (GI50 ~20 nM, 45-fold selective) and SDMA modulation (IC50​ ~3.4 nM, 147-fold selective) in MTAP-del cells compared to MTAP-WT cells.[2] This pattern is mirrored in vivo, where HSK-41959 induces significant tumor growth inhibition and SDMA modulation in MTAP-del xenografts but not in MTAP-WT xenografts at similar dosages.[2] This consistent pattern across biochemical, cellular, and animal models strongly supports the proposed mechanism of action and highlights its therapeutic potential in the targeted patient population.

A critical differentiating factor for HSK-41959 appears to be its potential for reduced hematological toxicity. Hematologic adverse events were major dose-limiting toxicities for previous, non-selective PRMT5 inhibitors, stemming from the essential role of PRMT5 in normal hematopoietic cell function.[2] The MTA-cooperative mechanism is specifically designed to spare normal cells, including hematopoietic cells, which do not accumulate MTA.[2] The more than 15-fold higher IC50​ of HSK-41959 against CD34+ cells compared to a first-generation inhibitor (544 nM vs 35.39 nM) [2] offers direct preclinical evidence supporting this hypothesis of an improved safety margin. If this reduced hematological toxicity translates to the clinical setting, it could represent a major advancement for this class of targeted therapies.

Table 2: Key Preclinical Efficacy and Selectivity Data for HSK-41959

Parameter	Value	Selectivity Fold (MTAP-del vs MTAP-WT)	Source(s)
PRMT5 IC50​ (with MTA)	0.80 nM	N/A	2
HCT116 Cell Growth GI50 (MTAP-del)	19.89 nM	~45-fold	2
HCT116 SDMA IC50​ (MTAP-del)	3.39 nM	~147-fold	2
HCT116 SDMA IC50​ (MTAP-WT)	499 nM	N/A	2
CD34+ HSC Proliferation IC50​ (HSK-41959)	544 nM	>15-fold vs Gen 1 PRMT5i	2
CD34+ HSC Proliferation IC50​ (Gen 1 PRMT5i)	35.39 nM	N/A	2
TGI (HCT116 MTAP-del, 25 mg/kg PO QD)	62%	Selective vs MTAP-WT	2
SDMA Inhibition (HCT116 MTAP-del, 25 mg/kg)	89%	Selective vs MTAP-WT	2
TGI (HCT116 MTAP-del, 100 mg/kg PO QD)	88%	Selective vs MTAP-WT	2
SDMA Inhibition (HCT116 MTAP-del, 100 mg/kg)	95%	Selective vs MTAP-WT	2
TGI (HCT116 MTAP-WT, 100 mg/kg PO QD)	No inhibition	N/A	2

4. Clinical Development Program: NCT06968572 (HSK41959-101)

Following promising preclinical results, HSK-41959 has advanced into clinical development with the initiation of a Phase 1 trial.

4.1. Trial Design and Objectives

The first-in-human study of HSK-41959 is registered under the identifier NCT06968572 and is also known by the internal study code HSK41959-101.[1] This is a Phase 1, open-label study designed to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of orally administered HSK-41959 in patients with MTAP-deleted locally advanced or metastatic solid tumors.[1]

The trial is structured in two main parts:

• Phase Ia (Dose Escalation and Extension):
• Part A (Dose Escalation): This part follows a standard "3+3" dose-escalation design. Small cohorts of patients receive escalating doses of HSK-41959 to determine the safety profile and identify dose-limiting toxicities (DLTs).[7]
• Part B (Dose Extension): Based on the findings from Part A, selected dose levels may be expanded to include additional patients (up to 10 subjects per cohort in this part). This extension allows for a more thorough investigation of the tolerability, PK, and PD characteristics of HSK-41959 at these chosen doses.[7] Approximately 30-50 subjects are planned for enrollment in the entirety of Phase Ia.
• Phase Ib (Dose Expansion): Once one or more safe and tolerable dose(s) are identified from Phase Ia, Phase Ib will commence. This phase involves enrolling larger cohorts of patients (no less than 10-50 subjects per expansion cohort) with specific MTAP-deleted locally advanced or metastatic solid tumors. Patients in these cohorts will receive HSK-41959 monotherapy at the dose level(s) determined in Phase Ia.[7] The primary aim of this phase is to further evaluate safety and to gather preliminary evidence of anti-tumor activity in defined tumor types.

The overarching objective is to determine the maximum tolerated dose (MTD) and/or the recommended Phase 2 dose (RP2D) of HSK-41959, while thoroughly characterizing its safety profile and how the drug is processed by the body (PK) and its effects on the body, including target engagement (PD).[6] A secondary objective, particularly for the dose expansion phase, is to assess the preliminary anti-tumor efficacy of HSK-41959.

4.2. Patient Population and Key Eligibility Criteria

The trial is designed to enroll adult patients with histologically or cytologically confirmed locally advanced or metastatic solid tumors who have experienced disease progression following standard treatment or are intolerant to standard therapies.[7]

Key Inclusion Criteria include:

• Age ≥ 18 years.[7]
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, indicating patients are fully ambulatory and capable of self-care.[7]
• Life expectancy of at least 3 months.[7]
• Crucially, patients must have a confirmed homozygous deletion of the MTAP gene in their tumor tissue, detected prior to the administration of HSK-41959.[6] This underscores the biomarker-driven nature of the trial.
• Presence of measurable disease as per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1).[7]
• Adequate organ function, including hematologic, hepatic, and renal parameters.[7]

Key Exclusion Criteria include:

• Prior treatment with any PRMT5 inhibitor or MAT2A inhibitor.[7]
• Presence of unstable or clinically symptomatic central nervous system (CNS) metastases, or leptomeningeal metastases.[7]
• History of other malignant tumors within the past 2 years, with certain exceptions such as adequately treated cutaneous squamous cell carcinoma, cervical carcinoma in situ, or papillary thyroid carcinoma.[7]
• Insufficient washout periods from prior anti-tumor therapies (e.g., generally 4 weeks or 5 half-lives for most drugs, 6 weeks for nitrosoureas or mitomycin C, and 2 weeks for palliative radiotherapy or anti-tumor herbal medicines).[7]
• Unresolved toxicities from previous treatments exceeding CTCAE Grade 1 (with some exceptions like alopecia or certain dermal toxicities deemed not to pose a safety risk).[7]
• Clinically significant or uncontrolled cardiac conditions, including QTc interval ≥ 450 msec for males or ≥ 470 msec for females, recent myocardial infarction, unstable angina, or New York Heart Association (NYHA) Class III/IV cardiac failure within 6 months prior to enrollment.[7]
• Cognitive dysfunction, history of severe mental illness, other uncontrolled comorbidities, alcohol dependence, or drug abuse.[7]

These eligibility criteria are largely standard for Phase 1 oncology trials involving patients with advanced solid tumors, with the addition of the mandatory MTAP gene deletion status as a key patient selection factor, reinforcing the targeted therapeutic approach of HSK-41959.

4.3. Primary and Secondary Outcome Measures

While the provided research material [7] outlines the study's objectives to evaluate safety, tolerability, PK, and PD, a detailed, official list of primary and secondary endpoints for NCT06968572 is not fully enumerated. Standard Phase 1 oncology trial design typically includes the following:

• Primary Outcome Measures (Phase Ia - Dose Escalation):
• Incidence and severity of Dose-Limiting Toxicities (DLTs).
• Determination of the Maximum Tolerated Dose (MTD) and/or Recommended Phase 2 Dose (RP2D).
• Overall safety and tolerability, assessed by the nature, frequency, and severity of Adverse Events (AEs) according to Common Terminology Criteria for Adverse Events (CTCAE).
• Secondary Outcome Measures (Phase Ia and Ib):
• Pharmacokinetic (PK) parameters of HSK-41959 (e.g., Cmax​, AUC, t1/2​, accumulation).
• Pharmacodynamic (PD) markers, likely including modulation of SDMA levels in peripheral blood and/or tumor tissue to confirm target engagement.
• Preliminary anti-tumor activity, including:
• Objective Response Rate (ORR) per RECIST 1.1.
• Duration of Response (DOR).
• Disease Control Rate (DCR).
• Progression-Free Survival (PFS).

It is important to note that while general definitions for primary and secondary endpoints are available (e.g., from ClinicalTrials.gov definitions [13] or examples from other trials [15]), these do not substitute for the specific, protocol-defined endpoints of NCT06968572.

4.4. Current Status, Enrollment, and Study Locations

• Current Status: The NCT06968572 trial is actively recruiting participants.[1]
• Estimated Enrollment: The study aims to enroll approximately 245 patients across both Phase Ia and Phase Ib.[7]
• Phase Ia is expected to enroll approximately 30-50 subjects.
• Phase Ib will enroll no less than 10-50 subjects in each tumor-specific expansion cohort.
• Study Timelines:
• One source indicates a study start date of April 11, 2025 [17], though this may be a database projection as regulatory approval in China was announced earlier.
• The primary completion date is listed by one database as March 26, 2026.[12]
• Another source estimates the study completion date as May 08, 2028.[6] The discrepancy in completion dates (2026 vs. 2028) is notable. Given the multi-part nature of a Phase 1 trial involving dose escalation and multiple expansion cohorts, a timeline extending over several years is plausible. The 2028 date might reflect the completion of all cohorts and follow-up, whereas the 2026 date could pertain to the primary completion of an earlier part of the study or specific cohorts.
• Study Locations: The trial is currently being conducted in China. Confirmed and enrolling sites include [7]:
• Shanghai East Hospital, Shanghai.
• Nanjing Drum Tower Hospital, Nanjing, Jiangsu. One additional site, The Affiliated Hospital of Guizhou Medical University in GuiYang, Guizhou, is listed as "Not yet enrolling" in one source [7] but implied as enrolling in another.[7] The initiation of the trial in China is consistent with Haisco Pharmaceutical Group being a Chinese company and having received the necessary regulatory clearance from the NMPA.

4.5. Regulatory Context in China

HSK-41959 tablets received an "Approval Notice for Drug Clinical Trials" from the National Medical Products Administration (NMPA) of China, which was announced on or around March 26 (year not definitively specified but likely 2024 or early 2025 based on context).[3] This approval signifies the NMPA's authorization for Haisco to commence human clinical trials with HSK-41959 in China. The drug is classified as a Class 1 Chemical Drug by the NMPA, a designation that underscores its novelty and indicates it has not been previously marketed in China or elsewhere.[3]

The initial clinical development of HSK-41959 is commencing in China. This strategy is common for Chinese pharmaceutical companies developing innovative assets and may be influenced by the location of the parent company, access to a potentially large and relevant patient pool with MTAP-deleted cancers, and a regulatory environment that can be supportive of innovative oncology drugs. Successful outcomes in these initial Chinese trials could then form the basis for subsequent global regulatory submissions and clinical trials in other regions, such as the US and EU. Haisco Pharmaceutical Group's establishment of Haisco-USA Pharmaceuticals, Inc. in 2020, with a focus on drug development in the US and EU, suggests a potential pathway for such ex-China development.[4]

Table 3: Overview of Clinical Trial NCT06968572 (HSK41959-101)

Feature	Details	Source(s)
Trial ID	NCT06968572, HSK41959-101	1
Phase	Phase 1	1
Title	A Phase I, Open-label, Dose-escalation and Expansion Study to Evaluate the Safety, Tolerability, Pharmacokinetic and Pharmacodynamic of HSK41959 in Patients With MTAP Deletion Locally Advanced or Metastatic Solid Tumors	1
Sponsor	Haisco Pharmaceutical Group Co., Ltd. / Shanghai Haisishengnuo Pharmaceutical Technology Co., Ltd.	1
Overall Objective	Evaluate safety, tolerability, PK, PD, and preliminary anti-tumor activity of HSK41959	6
Key Population	Adults with MTAP-deleted locally advanced or metastatic solid tumors, failed standard treatment	6
Intervention	HSK-41959 (oral monotherapy)	7
Design	Phase Ia (dose escalation "3+3" & dose extension), Phase Ib (dose expansion)	7
Current Status	Recruiting	1
Estimated Enrollment	~245 patients	7
Key Locations	China (Shanghai, Nanjing, GuiYang)	7
Est. Primary Completion	March 2026 (Ozmosi)	12
Est. Study Completion	May 2028 (TrialScreen)	6

5. Competitive Landscape: MTA-Cooperative PRMT5 Inhibitors

The development of HSK-41959 occurs within an active and competitive field focused on MTA-cooperative PRMT5 inhibitors for MTAP-deleted cancers.

5.1. Overview of the Therapeutic Strategy

The therapeutic strategy of targeting PRMT5 in cancers with MTAP deletion through MTA-cooperative inhibition is a well-recognized and actively pursued approach in contemporary oncology research.[8] This strategy is founded on the principle of synthetic lethality, aiming to selectively eliminate cancer cells harboring the MTAP deletion while sparing normal cells. A key anticipated advantage of this approach is an improved therapeutic index compared to earlier, non-selective PRMT5 inhibitors, which were often limited by on-target toxicities in normal tissues.[8] The presence of multiple pharmaceutical companies investing in and developing drugs based on this specific mechanism underscores the perceived validity of the target and the potential clinical utility of this approach. However, it also signifies a competitive environment where differentiation will be crucial.

5.2. Profile of Key Competitors

Several companies are advancing MTA-cooperative PRMT5 inhibitors through preclinical and clinical development.

• Tango Therapeutics:
• TNG908 and TNG462: These compounds were identified through high-throughput screening (HTS) and structure-based drug design efforts, specifically aimed at MTA-cooperative inhibition of PRMT5. TNG462 is highlighted as a potential best-in-class PRMT5 inhibitor.[10] In preclinical models, TNG462 demonstrated 45-fold greater potency in MTAP-deleted cancer cells (GI50 of 4 nM) compared to normal cells.[8] A Phase 1/2 clinical trial evaluating TNG462 as a monotherapy is ongoing, with a data update anticipated in the second half of 2025, focusing on pancreatic and lung cancer. Tango Therapeutics plans to initiate a registrational study for TNG462 in pancreatic cancer in the subsequent year.[18] Furthermore, a combination trial of TNG462 with Revolution Medicines' RAS(ON) inhibitors (daraxonrasib and zoldonrasib) is expected to commence enrollment in the second quarter of 2025, targeting pancreatic and lung cancers.[18]
• TNG456: This is described as a next-generation, potent, and blood-brain barrier (BBB) penetrant PRMT5 inhibitor. It exhibits selectivity for MTAP-deleted cells similar to TNG462 (55-fold greater potency in MTAP-deleted cells, GI50 of 20 nM).[8] A Phase 1/2 clinical trial for TNG456 is expected to start enrollment in the second quarter of 2025, with a focus on glioblastoma and other MTAP-deleted solid tumors where BBB penetration is advantageous.[8]
• Mirati Therapeutics (acquired by Bristol Myers Squibb):
• MRTX1719 (also known as BMS-986504): This is another MTA-cooperative PRMT5 inhibitor that has progressed into clinical trials.[9] Preclinically, MRTX1719 selectively inhibited PRMT5 in HCT116 MTAP-deleted cells with over 70-fold selectivity compared to MTAP wild-type cells.[9] The ongoing Phase 1/2 trial (NCT05245500) has shown encouraging early efficacy data, including confirmed objective responses in patients with various MTAP-deleted solid tumors (such as NSCLC, cholangiocarcinoma, and melanoma), and the drug has been well-tolerated with no dose-limiting toxicities observed up to 400mg once daily.[21] Initiation of a Phase 2 study was anticipated in the first half of 2024.[21] An abstract from ASCO 2025 indicated that MRTX1719, when combined with an anti-PD-1 antibody, demonstrated slowed tumor growth and extended survival in MTAP-loss syngeneic murine models, supporting its potential in immuno-oncology combinations.[26]
• Amgen:
• AMG 193: This is Amgen's MTA-cooperative PRMT5 inhibitor.[10] AMG 193 preferentially inhibits PRMT5 when it is complexed with MTA.[27] In an ongoing Phase 1/2 study, AMG 193 has demonstrated promising clinical activity, including confirmed partial responses in patients with various MTAP-deleted solid tumors, such as pancreatic adenocarcinoma and NSCLC (squamous and non-squamous).[27] A Phase II study of AMG 193 in patients with MTAP-null advanced NSCLC has been initiated and is currently enrolling participants.[28] A planned combination trial of AMG 193 with the MAT2A inhibitor IDE397 (from Ideaya Biosciences) was discontinued.[28]
• Other Emerging Competitors:
• The clinical landscape also includes other companies such as CytosinLab with CTS3497 and PharmaEngine with PEP08, both of which are developing PRMT5 inhibitors for MTAP-deleted cancers and are reportedly entering Phase 1 clinical studies.[17]

The field of MTA-cooperative PRMT5 inhibitors is evidently becoming more populated, with several candidates advancing through clinical trials. Differentiation among these agents will likely hinge on a combination of factors. These include demonstrable differences in potency and selectivity, the breadth of anti-tumor activity across various MTAP-deleted cancer types, the overall safety and tolerability profile (with particular attention to hematologic and, for BBB-penetrant compounds, neurological adverse events), oral bioavailability and pharmacokinetic properties influencing dosing schedule convenience, and, critically, efficacy when used in combination regimens. Given the complexity of cancer, combination therapies are often essential for durable responses, and the ability of these PRMT5 inhibitors to synergize with other targeted agents or immunotherapies could be a key determinant of their ultimate clinical success and market positioning.

While HSK-41959 has demonstrated promising preclinical selectivity (e.g., 147-fold selectivity for SDMA inhibition in MTAP-del vs. MTAP-WT cells) [2], direct, head-to-head preclinical comparisons with leading competitor compounds under standardized assay conditions would be highly informative for assessing its relative standing. The currently available abstract for HSK-41959 [2] compares its heme toxicity to "first-generation PRMT5i" but does not offer direct comparative data against other MTA-cooperative inhibitors on other parameters. Competitors like TNG462 and MRTX1719 also report high selectivity (45-fold and >70-fold, respectively).[8] Although clinical data will be the ultimate arbiter of superiority, comprehensive and comparative preclinical data can aid in early-stage evaluation and de-risking. Haisco Pharmaceutical Group may possess such internal comparative data not disclosed in the provided materials.

Table 4: Comparative Snapshot of Select MTA-Cooperative PRMT5 Inhibitors

Drug Name	Developer(s)	Highest Development Phase	Key Reported Selectivity (MTAP-del vs WT)	Key Reported Clinical Activity (if available)	Notable Features	Source(s)
HSK-41959	Haisco Pharmaceutical Group	Phase 1	~45-fold (cell growth GI50); ~147-fold (SDMA IC50​)	Phase 1 ongoing; no clinical data reported in snippets.	Oral administration; potentially lower heme toxicity vs Gen 1.	1
TNG462	Tango Therapeutics	Phase 1/2	45-fold (potency, 4 nM in MTAP-del)	Phase 1/2 ongoing; data update 2H 2025 (pancreatic, lung).	Potential best-in-class; combination with RAS(ON) inhibitors planned.	8
TNG456	Tango Therapeutics	Phase 1/2 (planned 2Q 2025)	55-fold (potency, 20 nM in MTAP-del)	Phase 1/2 enrollment expected 2Q 2025.	BBB-penetrant, focus on glioblastoma, NSCLC.	8
MRTX1719	Mirati Therapeutics (Bristol Myers Squibb)	Phase 1/2	>70-fold (cell viability)	Confirmed objective responses in Phase 1/2 (NSCLC, cholangio, melanoma); well-tolerated up to 400mg QD. Phase 2 initiation expected 1H 2024. Combination with anti-PD-1 showed preclinical synergy.	Potential first-in-class; encouraging early efficacy.	9
AMG 193	Amgen	Phase 2	Preferentially inhibits PRMT5•MTA complex	Confirmed partial responses in Phase 1/2 (various MTAP-del solid tumors, incl. pancreatic, NSCLC). Phase 2 in MTAP-null advanced NSCLC enrolling. Combination with MAT2A inhibitor discontinued.	Promising clinical activity across multiple tumor types.	10
CTS3497	CytosinLab	Phase 1 (planned)	N/A in snippets	Phase 1 planned for MTAP-deficient malignancies.	Emerging player.	17
PEP08	PharmaEngine	Phase 1 (planned)	N/A in snippets	Phase 1 planned for MTAP-deleted cancers.	Emerging player.	17

N/A: Not Available in the provided snippets.

6. Summary and Future Perspectives

6.1. Key Attributes and Potential of HSK-41959

HSK-41959 has emerged as an orally bioavailable, MTA-cooperative PRMT5 inhibitor, distinguished by its promising preclinical profile. This includes marked selectivity for MTAP-deleted cancer cells and indications of a potentially improved safety margin, particularly concerning heme-related toxicities, when compared to earlier-generation, non-selective PRMT5 inhibitors.[1] Its mechanism of action, which leverages the accumulation of MTA in MTAP-deficient tumors, allows for targeted inhibition of PRMT5, a critical enzyme in cancer cell proliferation and survival. The compound has demonstrated significant, dose-dependent anti-tumor activity in MTAP-deleted xenograft models while sparing MTAP wild-type models, providing a strong rationale for its clinical investigation.[2] HSK-41959 is currently advancing through Phase 1 clinical development in China under the trial identifier NCT06968572, with the primary goals of assessing its safety, tolerability, pharmacokinetics, and pharmacodynamics, as well as preliminary efficacy in patients with MTAP-deleted advanced solid tumors.[1]

6.2. Unmet Needs in MTAP-Deleted Cancers

The homozygous deletion of the MTAP gene is a relatively common oncogenic event, identified in approximately 10-15% of all human cancers. This genetic alteration is prevalent across a spectrum of difficult-to-treat malignancies, including various types of lung cancer, pancreatic cancer, mesothelioma, and glioblastoma.[2] Despite this prevalence, there is a significant unmet medical need for effective targeted therapies specifically designed for this large, genetically defined patient population. The development of MTA-cooperative PRMT5 inhibitors like HSK-41959 aims to address this gap, offering a precision oncology approach that could lead to more effective and less toxic treatments for these patients. The successful clinical development of such agents holds the potential for substantial patient impact.

6.3. Concluding Remarks on Development Trajectory

The progression of HSK-41959 into Phase 1 clinical trials marks a critical milestone in its development. The immediate focus of these trials will be to establish the MTD, further characterize the safety profile, and understand the pharmacokinetic and pharmacodynamic behavior of HSK-41959 in human subjects. Beyond establishing initial safety and determining the appropriate dose for further studies, a key set of questions will guide the subsequent clinical development of HSK-41959. Central to this will be a thorough comparison of its clinical safety profile, especially concerning hematologic toxicities, against those of other MTA-cooperative PRMT5 inhibitors that are also in development. The objective response rates and the durability of these responses across various MTAP-deleted tumor types, which will be assessed in the Phase 1b expansion cohorts, will be critical indicators of its therapeutic potential. Identifying specific MTAP-deleted tumor histologies where HSK-41959 demonstrates exceptional activity could refine its development path and target patient population. Furthermore, the validation of optimal pharmacodynamic biomarkers in patient samples will be essential for confirming target engagement, understanding the mechanism of action in humans, and potentially predicting clinical response or guiding dose optimization. Given that combination therapies are the cornerstone of modern oncology treatment, exploring and identifying synergistic combination strategies for HSK-41959 will also be vital for its long-term success and ability to address complex resistance mechanisms.

The competitive landscape for MTA-cooperative PRMT5 inhibitors is active, with several candidates progressing through clinical trials.[8] This underscores the need for HSK-41959 to demonstrate a clear differentiation, which could be based on superior efficacy in specific tumor types, an improved safety and tolerability profile, more convenient dosing, or enhanced activity when used in combination with other anti-cancer agents.

While the initial clinical development of HSK-41959 is centered in China [7], the global prevalence of MTAP-deleted cancers and the international activities of its competitors suggest that a broader, global development strategy will likely be necessary for Haisco Pharmaceutical Group to maximize the drug's potential impact and market access. The existence of Haisco-USA Pharmaceuticals, Inc., established in 2020 with a focus on drug development in the US and EU [4], may provide a conduit for such ex-China clinical trials and regulatory submissions to agencies like the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Successful development and approval of HSK-41959 would represent a significant advancement, offering a novel, biomarker-guided therapeutic option for a substantial subset of cancer patients with high unmet medical needs.

Executive Summary

HSK-41959 is an orally administered, investigational small molecule drug developed by Haisco Pharmaceutical Group Co., Ltd., currently in Phase 1 clinical development (NCT06968572) in China for the treatment of locally advanced or metastatic solid tumors harboring methylthioadenosine phosphorylase (MTAP) gene deletions.[1] Classified as a Class 1 Chemical Drug by China's NMPA, HSK-41959 functions as a potent and selective methylthioadenosine (MTA)-cooperative Protein Arginine Methyltransferase 5 (PRMT5) inhibitor.[2]

The scientific rationale for HSK-41959 is rooted in the synthetic lethality observed in MTAP-deleted cancers. MTAP deletion, occurring in 10-15% of human cancers, leads to the accumulation of MTA within cancer cells.[2] MTA acts as a partial endogenous inhibitor of PRMT5. HSK-41959 is designed to preferentially bind to and inhibit the MTA-bound PRMT5 complex, thereby selectively targeting cancer cells with high MTA levels while sparing normal cells with low MTA levels.[2] This MTA-cooperative mechanism aims to overcome the dose-limiting hematologic toxicities associated with first-generation, non-selective PRMT5 inhibitors, potentially offering an improved therapeutic index.[2]

Preclinical studies have demonstrated HSK-41959's promising profile. In vitro, it showed an IC50​ of 0.80 nM for PRMT5 inhibition in the presence of MTA and exhibited significant selectivity for MTAP-deleted HCT116 colon cancer cells, with approximately 45-fold selectivity in growth inhibition (GI50 19.89 nM) and 147-fold selectivity in SDMA inhibition (IC50​ 3.39 nM in MTAP-del vs. 499 nM in MTAP-WT cells).[2] Importantly, HSK-41959 demonstrated significantly lower toxicity against CD34+ hematopoietic stem cells (IC50​ 544 nM) compared to a first-generation PRMT5 inhibitor (IC50​ 35.39 nM), suggesting a reduced potential for heme-related adverse events.[2] In vivo, HSK-41959 induced dose-dependent tumor growth inhibition (up to 88% TGI at 100 mg/kg) and robust target engagement (up to 95% SDMA inhibition) in MTAP-deleted xenograft models, with no efficacy observed in MTAP wild-type models at similar doses.[2]

The ongoing Phase 1 trial (NCT06968572) is an open-label, dose-escalation (Phase Ia) and dose-expansion (Phase Ib) study designed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary anti-tumor activity of HSK-41959 in patients with MTAP-deleted advanced solid tumors.[1] Key objectives include determining the MTD and RP2D. The trial is actively recruiting an estimated 245 patients in China.[1]

HSK-41959 enters a competitive field of MTA-cooperative PRMT5 inhibitors, with notable candidates including TNG462 and TNG456 (Tango Therapeutics), MRTX1719 (Bristol Myers Squibb, formerly Mirati Therapeutics), and AMG 193 (Amgen), all of which are in clinical development and have shown promising early data.[8] Differentiation will depend on clinical efficacy, safety, and potential combination strategies.

Successful clinical development of HSK-41959 could offer a valuable new targeted therapy for a significant and underserved patient population characterized by MTAP gene deletion. Future development will likely focus on confirming its safety and efficacy profile, identifying optimal tumor indications, and potentially exploring global regulatory pathways.

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