NKT-2152: An Investigational HIF2α Inhibitor for Advanced Solid Tumors

1. Executive Summary of NKT-2152

NKT-2152 is an orally bioavailable, small molecule investigational therapeutic agent designed to inhibit Hypoxia-Inducible Factor 2α (HIF2α), a transcription factor implicated as a key oncogenic driver in various malignancies. Developed by NiKang Therapeutics® Inc., NKT-2152 is currently undergoing clinical evaluation for the treatment of advanced solid tumors, with a pronounced focus on clear cell Renal Cell Carcinoma (ccRCC) and Hepatocellular Carcinoma (HCC).[1]

The development program for NKT-2152 has yielded significant preclinical anti-tumor activity and has progressed to demonstrate promising efficacy signals in early-phase human clinical trials. These positive signals are particularly evident in heavily pretreated ccRCC patient populations, an area with substantial unmet medical need. A distinguishing characteristic of NKT-2152 is its unique pharmacokinetic (PK) profile, notably featuring a long terminal half-life, which is believed to support sustained target engagement and may offer dosing advantages.[1] The clinical development of NKT-2152 is robust, encompassing investigations of the agent both as a monotherapy and in various combination regimens. This comprehensive program is supported by strategic collaborations with several major pharmaceutical companies, facilitating broader and more rapid evaluation.

NKT-2152 holds the potential to emerge as a novel therapeutic option for cancers characterized by dysregulation of the HIF2α pathway. Its mechanism aims to address the underlying drivers of tumor growth and progression in specific patient cohorts who currently have limited or ineffective treatment alternatives. The strategic decision to develop NKT-2152 concurrently for ccRCC, where the role of HIF2α is well-established due to frequent von Hippel-Lindau (VHL) gene mutations [5], and for HCC, a malignancy with a more heterogeneous molecular landscape where HIF2α's role is an area of active investigation [1], reflects a multifaceted development strategy. This approach leverages the strong biological rationale in ccRCC while simultaneously exploring the broader therapeutic applicability of NKT-2152. Such diversification, supported by compelling preclinical data across different tumor types and a favorable pharmacological profile, could enhance the drug's overall clinical and market potential by addressing multiple unmet needs.

2. NKT-2152: Drug Profile and Mechanism of Action

NKT-2152 is an investigational small molecule drug candidate characterized by its oral bioavailability and its targeted mechanism as an inhibitor of HIF2α.

Chemical Nature and Formulation:

NKT-2152 is classified as a small molecule compound.1 It has been formulated for oral administration, offering the potential for patient convenience.1 Specific details regarding the exact chemical structure, tablet strengths, or comprehensive pharmaceutical formulation excipients are not detailed in the available documentation.

Developer and Commercial Interests:

The primary developer of NKT-2152 is NiKang Therapeutics® Inc., a clinical-stage biotechnology company dedicated to the discovery and development of innovative small molecule oncology medicines.1 Jiangsu Hansoh Pharmaceutical Group Company Limited (Hansoh Pharma) has secured commercial interests in NKT-2152 through a strategic collaboration and license agreement. This agreement, announced around May 3, 2022, grants Hansoh Pharma rights for the development and commercialization of NKT2152 in Greater China, which includes mainland China, Hong Kong, Macau, and Taiwan.4

Key Strategic Collaborations:

NiKang Therapeutics has entered into several key collaborations to advance the clinical development of NKT-2152:

• Roche (F. Hoffmann-La Roche Ltd): A clinical trial collaboration and supply agreement is active for the evaluation of NKT2152 in combination with Roche's standard-of-care regimen, consisting of atezolizumab (an anti-PD-L1 monoclonal antibody) and bevacizumab (an anti-VEGF monoclonal antibody). This combination is being studied as a first-line treatment for patients with unresectable or advanced HCC within Roche's MORPHEUS-liver multi-arm platform trial (NCT04524871).[1]
• Pfizer Inc.: On November 30, 2021, NiKang Therapeutics announced a clinical trial collaboration and supply agreement with Pfizer. This partnership aims to evaluate NKT2152 in novel combination therapies for the treatment of advanced ccRCC.[15]
• AVEO Oncology (now part of LG Chem): A clinical trial collaboration and supply agreement was established with AVEO Oncology, announced on January 5, 2022. This collaboration focuses on evaluating NKT2152 in combination with FOTIVDA® (tivozanib), a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI), for the treatment of advanced ccRCC. Under this agreement, NiKang Therapeutics serves as the trial sponsor, with AVEO providing co-funding.[18]

Detailed Mechanism of Action (MoA):

NKT-2152 is engineered as a highly potent and selective inhibitor of Hypoxia-Inducible Factor 2α (HIF2α).1 Its MoA involves several key steps:

1. Allosteric Binding: NKT-2152 binds to the HIF2α protein at an allosteric site. This site is distinct from the regions directly involved in DNA binding or interaction with its dimerization partner, HIF1β. This binding induces a conformational change in the HIF2α protein.[1] The allosteric nature of this interaction may contribute to the inhibitor's selectivity and potentially offer advantages in overcoming certain resistance mechanisms that could arise with orthosteric inhibitors targeting active sites directly.
2. Disruption of Heterodimerization: The conformational change induced by NKT-2152 binding disrupts the crucial heterodimerization of HIF2α with its obligate partner, HIF1β (also known as Aryl Hydrocarbon Receptor Nuclear Translocator, ARNT).[1] The formation of this HIF2α/HIF1β complex is a prerequisite for its function as an active transcription factor.
3. Inhibition of Transcriptional Activity: By preventing the formation of the functional HIF2α/HIF1β heterodimer, NKT-2152 effectively blocks the ability of this complex to bind to Hypoxia Response Elements (HREs) located in the promoter and enhancer regions of its target genes. This, in turn, leads to a significant reduction in the transcription and subsequent cellular production of a wide array of downstream proteins.[1] Targeting this fundamental step of heterodimerization provides a comprehensive approach to abrogating the entire downstream transcriptional program driven by HIF2α, rather than merely modulating a single aspect of its activity.
4. Downstream Effects: The target genes regulated by HIF2α are critically involved in multiple facets of tumorigenesis and tumor progression. These include processes such as angiogenesis (e.g., vascular endothelial growth factor, VEGF), cellular proliferation and survival, metabolic reprogramming (particularly enhanced glycolysis), and invasion and metastasis. By downregulating these pathways, NKT-2152 aims to inhibit tumor growth and spread.

The MoA of NKT-2152 is particularly pertinent in ccRCC. A high percentage of ccRCC cases are characterized by the biallelic inactivation (through mutation, deletion, or hypermethylation) of the von Hippel-Lindau (VHL) tumor suppressor gene. Under normal oxygen conditions (normoxia), the VHL protein (pVHL) is a key component of an E3 ubiquitin ligase complex that recognizes and targets HIFα subunits (including HIF2α) for proteasomal degradation. When pVHL is non-functional, HIF2α accumulates constitutively, irrespective of oxygen availability, leading to its persistent activation and the promotion of ccRCC pathogenesis.[5] NKT-2152 directly counteracts this pathological accumulation and activity of HIF2α.

Table 1: NKT-2152: Key Drug Characteristics, Developer, and Strategic Alliances

Characteristic	Details	Key Snippet(s) for Information
Drug Type	Small Molecule	1
Administration Route	Oral	1
Core MoA	Selective Allosteric Inhibitor of Hypoxia-Inducible Factor 2α (HIF2α)	1
Developer	NiKang Therapeutics® Inc.	1
Commercial Rights	Jiangsu Hansoh Pharmaceutical Group (Greater China)	4
Key Collaborator 1	Roche (F. Hoffmann-La Roche Ltd)	1
Focus of Collaboration 1	Combination with Atezolizumab/Bevacizumab in 1L HCC (MORPHEUS-Liver Trial - NCT04524871)	1
Key Collaborator 2	Pfizer Inc.	15
Focus of Collaboration 2	Novel combination therapies for advanced ccRCC	15
Key Collaborator 3	AVEO Oncology (LG Chem)	18
Focus of Collaboration 3	Combination with Tivozanib (FOTIVDA®) for advanced ccRCC	18

3. Preclinical Evaluation of NKT-2152

The progression of NKT-2152 into clinical trials is underpinned by a body of preclinical research demonstrating its anti-tumor activity and favorable pharmacological properties.

Broad Anti-Tumor Potential:

Preclinical investigations have indicated that NKT-2152 possesses broad anti-tumor activity across a range of xenograft models. This activity is not limited to ccRCC, the classical HIF2α-driven malignancy, but extends to other solid tumor types, thereby supporting its clinical evaluation in diverse oncological indications.1 NiKang Therapeutics presented comprehensive preclinical data at the American Association for Cancer Research (AACR) Annual Meeting in 2022. This presentation detailed NKT2152's mechanism of action, its in vivo pharmacokinetic and pharmacodynamic profiles, and its anti-tumor efficacy in multiple cancer models.15 The early demonstration of efficacy in non-ccRCC models, such as HCC, is a significant indicator of NKT-2152's potential for broader applicability, suggesting that HIF2α dysregulation or sensitivity to its inhibition may be relevant in a wider array of cancers than initially appreciated.

Activity in Specific Tumor Models:

• Clear Cell Renal Cell Carcinoma (ccRCC): NKT-2152 has demonstrated robust anti-tumor effects in preclinical models of ccRCC. These include studies utilizing both ccRCC cell line-derived xenografts (CDX) and patient-derived xenograft (PDX) models.[3] The activity in PDX models is particularly encouraging, as these models are generally considered to more accurately reflect the heterogeneity and therapeutic response of human tumors compared to traditional cell line models. This is because PDX models often better preserve the original tumor architecture, genetic diversity, and tumor microenvironment components.
• Hepatocellular Carcinoma (HCC): Significant anti-tumor effects were also observed in preclinical HCC xenograft models.[16] These findings provided a strong scientific rationale for extending the clinical investigation of NKT-2152 into HCC, despite HCC having a more diverse molecular etiology than the typically VHL-mutant ccRCC.

Pharmacological Profile in Preclinical Studies:

Preclinical data have highlighted NKT2152's potential as a "best-in-class" agent, attributed to its excellent potency and a favorable pharmacokinetic profile.16 The molecule was specifically optimized during its discovery phase to achieve enhanced pharmacokinetic exposure and sustained target inhibition, which are desirable properties for an orally administered anti-cancer therapeutic.3

Table 2: Summary of Key NKT-2152 Preclinical Efficacy and MoA Findings

Tumor Model Type	Key Efficacy Outcome(s)	Mechanism of Action Insight(s)	Source/Presentation	Snippet ID(s)
ccRCC Xenografts	Significant anti-tumor activity	Inhibition of HIF2α pathway	NiKang Internal	3
(CDX and PDX)			AACR 2022	15
HCC Xenografts	Anti-tumor effect observed	Suggests broader applicability beyond VHL-mutant tumors; HIF2α pathway inhibition	AACR 2022	16
Multiple Xenograft	Broad anti-tumor activity; Potent; Favorable PK/PD profile	HIF2α inhibition; Optimized for enhanced PK exposure and sustained target inhibition	NiKang Internal	1
Models			AACR 2022	6

4. Clinical Development Program of NKT-2152

NKT-2152 is being evaluated in a comprehensive clinical development program that includes monotherapy and combination therapy trials across various cancer types, primarily focusing on ccRCC and HCC.

Table 3: NKT-2152 Clinical Trial Landscape

NCT Identifier	Trial Phase	Official Title / Brief Description	Indication(s)	Intervention(s)	Study Status (as of latest snippet)	Estimated / Actual Enrollment	Key Reported Results / Milestones / Primary Completion Date	Snippet ID(s)
NCT05119335	Phase 1/2	A Study of NKT2152, a HIF2α Inhibitor, in Patients with Advanced Clear Cell Renal Cell Carcinoma (ccRCC)	Advanced ccRCC	NKT2152 Monotherapy (various daily and loading/maintenance doses)	Active, not recruiting	113 (100 efficacy evaluable in some reports, 96 in ESMO 2024 abstract)	ORR: 20-26.3%; mPFS: 7.4-9.2 mos. Long half-life (~38 days). Safety consistent with class. Primary Completion: May 2025.	1
NCT05935748	Phase 2	A Phase 2 Trial to Evaluate the Safety and Efficacy of NKT2152 in Combination with Palbociclib (Doublet) and with Palbociclib and Sasanlimab (Triplet) in Subjects with Advanced or Metastatic Clear Cell Renal Cell Carcinoma	Advanced/Metastatic ccRCC	NKT2152 + Palbociclib; NKT2152 + Palbociclib + Sasanlimab	Active, not recruiting	Approx. N/A in snippets	Lead-in and Expansion phases. Primary Completion: June 2025.	1
NCT04524871	Phase 1b/2 (MORPHEUS-Liver Platform)	A Phase Ib/II, Open-Label, Multicenter, Randomized Umbrella Study Evaluating the Efficacy and Safety of Multiple Immunotherapy-Based Treatment Combinations in Patients With Advanced Liver Cancers (NKT2152 arm)	First-line Advanced/Metastatic Hepatocellular Carcinoma (HCC)	NKT2152 + Atezolizumab + Bevacizumab	Recruiting (NKT2152 arm)	N/A for specific arm in snippets (Overall trial large)	First patient in NKT2152 arm dosed Jan 2025. Primary Completion (overall trial): Dec 2026.	1
AVEO Collaboration Trial (NCT ID not specified in snippets)	Phase 2 (Planned)	Combination of NKT2152 and Tivozanib (FOTIVDA®)	Advanced ccRCC (Relapsed/Refractory)	NKT2152 + Tivozanib	Expected to commence in 2022	N/A in snippets	To evaluate safety and efficacy.	18

Clear Cell Renal Cell Carcinoma (ccRCC)

The development of NKT-2152 in ccRCC is multifaceted, involving monotherapy studies to establish its intrinsic activity and safety, followed by combination trials aiming to enhance efficacy and overcome potential resistance mechanisms. This strategy acknowledges the complexity of advanced ccRCC and the frequent necessity for multi-agent regimens.

• NCT05119335: Phase 1/2 Monotherapy Study
• Design and Objectives: This foundational study is an open-label, multicenter, first-in-human (FIH) trial. The Phase 1 component focused on dose escalation to determine the MTD and/or RDEs of NKT2152 as a single agent. The subsequent Phase 2 portion is designed to evaluate the anti-tumor efficacy, further characterize the safety profile, and assess the PK and PD of NKT2152 at the selected dose(s).[5]
• Patient Population: The trial enrolled adult patients with advanced or metastatic ccRCC who had progressed on, or were intolerant to, available standard therapies. This included patients who had received one or more prior lines of systemic treatment. Key eligibility criteria included an ECOG performance status of 0-2 and measurable disease according to RECIST v1.1. Patients with prior exposure to other HIF2α inhibitors or those requiring supplemental oxygen were typically excluded.[5]
• Endpoints: Primary endpoints were safety and tolerability (incidence of DLTs) in Phase 1, and ORR by RECIST v1.1 in Phase 2. Secondary endpoints encompassed PFS, DOR, DCR, OS, PK parameters, and PD markers such as EPO suppression.[14]
• Status and Enrollment: The trial is currently active but not recruiting participants.[4] Initial dose-escalation phases are complete, and dose-expansion cohorts have been evaluated. As of the ESMO 2024 Congress presentation (data cut-off February 20, 2024), 96 patients had been enrolled (71 in dose escalation, 25 in expansion).[23] Some later reports indicate a total of 113 patients investigated, with 100 being evaluable for efficacy analyses.[5]
• Efficacy Results (primarily from ESMO 2024 Congress, Jonasch E, et al.):
• In an efficacy-evaluable population of 81 patients (data cut-off Feb 2024), the confirmed ORR was 24% (95% CI: 15-34%).[23] Other analyses of a larger cohort (n=100 evaluable) reported an ORR of 20%, which included 1 complete response (CR) and 19 partial responses (PRs).[5]
• The dose-escalation cohort (n=57 evaluable patients) demonstrated an ORR of 26.3% (1 CR, 14 PRs).[5]
• Median PFS was reported as 7.5 months (95% CI: 3.7-13 months) in the 81-patient cohort [23], and 7.4 months in the 100-patient cohort.[5] For the dose-escalation cohort, median PFS was 9.2 months.[5]
• The 12-month PFS rate was 41.8% for the overall efficacy-evaluable population.[6]
• The median DOR was not reached at the time of the analyses.[6]
• The DCR was 60% (95% CI: 50-70%).[6]
• The median time to initial response was 3.7 months.[6]
• Notably, clinical activity was observed in a heavily pretreated patient population, with a median of 3 to 4 prior lines of therapy.[6] An ORR of ~20-26% in this setting is clinically relevant, particularly when considering the limited efficacy of available later-line treatments. This positions NKT-2152 as a potentially competitive agent within the HIF2α inhibitor class, comparable to agents like belzutifan which showed an ORR of 25% in a similar refractory population.[31]
• Trends toward better ORR were noted in patients with IMDC favorable risk, ECOG PS 0, and those who were naive to prior mTOR inhibitor therapy.[6]
• Safety and Tolerability (NCT05119335): The safety profile was generally manageable and consistent with the known class effects of HIF2α inhibitors. Common AEs included anemia, fatigue, and hypoxia. DLTs (fatigue and hypoxia) were observed in some loading/maintenance dose cohorts, leading to 14% of patients discontinuing due to AEs in one cohort analysis.[5] (Further details in Section 6).
• Dosage Regimens (NCT05119335): The study explored a range of daily doses (50 mg, 100 mg, 200 mg, 300 mg QD) and various loading/maintenance schedules (e.g., 200 mg QD for 7, 14, or 28 days, followed by 50 mg QD or 200 mg weekly). Two dose levels were ultimately selected for the randomized expansion phase.[6] The exploration of these varied dosing regimens is a direct consequence of NKT-2152's long half-life, aiming to optimize rapid attainment of therapeutic concentrations and maintain them effectively while managing tolerability.
• NCT05935748: Phase 2 Combination Study (NKT2152 + Palbociclib ± Sasanlimab)
• Design and Objectives: This Phase 2, open-label, multicenter, global study includes a lead-in phase for dose escalation and determination of the RDE, followed by an expansion phase. It evaluates NKT2152 in combination with palbociclib (a CDK4/6 inhibitor) and also as a triplet with palbociclib and sasanlimab (an anti-PD-1 antibody).[1]
• Patient Population: The trial enrolls adults with locally advanced or metastatic ccRCC who have progressed after at least one prior anti-VEGF/VEGFR systemic therapy and one prior ICI.[4]
• Status: The trial is active but not currently recruiting. The primary completion date is estimated to be June 2025.[3]
• Specific efficacy or safety results from NCT05935748 are not yet available in the provided documentation.
• Clinical Trial Collaboration with AVEO Oncology (NKT2152 + Tivozanib)
• Rationale: This collaboration is based on preclinical and early clinical data suggesting potential synergy and enhanced anti-tumor activity from the combined inhibition of the HIF2α and VEGFR pathways. Tivozanib (FOTIVDA®) is an established VEGFR TKI.[18]
• Study Design: A Phase 2 trial was planned to evaluate the safety and efficacy of NKT2152 plus tivozanib in ccRCC patients who are relapsed or refractory to prior therapies.[18]
• Status: The trial was anticipated to commence in 2022.[18] Further specific details, including an NCT number or progress updates for this AVEO combination trial, are not provided in the available information.

Hepatocellular Carcinoma (HCC)

The investigation of NKT-2152 in HCC marks a significant expansion beyond its initial focus on ccRCC, leveraging its MoA and favorable PK profile for combination therapies in a different tumor type with high unmet need.

• NCT04524871 (MORPHEUS-Liver Platform Trial): Phase 1b/2 Combination Study (NKT2152 + Atezolizumab + Bevacizumab)
• Design and Objectives: NKT-2152 is being evaluated as a distinct treatment arm within Roche's MORPHEUS-Liver study. This is a Phase 1b/II, open-label, multicenter, randomized umbrella platform trial designed to assess the efficacy and safety of multiple immunotherapy-based treatment combinations. The NKT2152 arm specifically investigates the drug in combination with the standard-of-care regimen of atezolizumab and bevacizumab.[1] The inclusion in a platform trial like MORPHEUS-Liver allows for efficient and adaptive evaluation of NKT-2152 in combination with an established standard of care in HCC, potentially accelerating its development in this indication.
• Patient Population: The study enrolls patients requiring first-line treatment for locally advanced or metastatic and/or unresectable HCC who are not candidates for curative surgical or locoregional therapies. Eligible patients must have an ECOG performance status of 0 or 1 and Child-Pugh class A liver function. No prior systemic therapy for HCC is permitted.[1]
• Status: The NKT2152 arm of the MORPHEUS-Liver trial is currently recruiting. NiKang Therapeutics announced the dosing of the first patient in this arm on January 21, 2025.[1] The overall MORPHEUS-Liver trial has an estimated primary completion date of December 2026.[4]
• Specific efficacy or detailed safety results for the NKT-2152 containing arm of NCT04524871 are not yet available in the provided documentation, beyond enrollment initiation and general eligibility criteria.[11]

Other Potential Solid Tumors:

Based on broad anti-tumor activity observed in preclinical studies, NiKang Therapeutics has indicated an interest in exploring the potential of NKT-2152 in other solid tumors beyond ccRCC and HCC, particularly those that may not have the classical VHL gene deficiency but might still exhibit sensitivity to HIF2α inhibition.1

5. Pharmacokinetics and Pharmacodynamics (PK/PD) of NKT-2152

The pharmacokinetic (PK) and pharmacodynamic (PD) profiles of NKT-2152 are critical aspects of its clinical development, influencing dosing strategies, efficacy, and safety.

Human Pharmacokinetic (PK) Profile:

NKT-2152 exhibits a distinct human PK profile that sets it apart from some other HIF2α inhibitors. Key characteristics include:

• High Systemic Exposure and Large Volume of Distribution: The drug achieves higher systemic exposure and has a larger volume of distribution.[1] A large volume of distribution often suggests good tissue penetration, which is advantageous for treating solid tumors.
• Long Terminal Half-Life: A notable feature is its significantly long terminal half-life (t½), estimated to be approximately 38 days. This estimation is based on a 2-compartment population PK model derived from data in the NCT05119335 study in ccRCC patients.[5] This extended half-life implies that the drug persists in the body for a considerable duration.
• Dose Linearity and Time Independence: In the Phase 1/2 ccRCC study (NCT05119335), the pharmacokinetics of NKT-2152 were found to be dose-linear and time-independent, meaning that exposure increases proportionally with dose and the drug's clearance does not change significantly over time with repeated dosing.[6]

The combination of these PK properties—high exposure, extensive distribution, and a very long half-life—suggests that NKT-2152 can achieve and maintain effective concentrations in tumor tissues for extended periods. This profile supports the investigation of dosing schedules that might be more convenient for patients, such as less frequent maintenance dosing, and makes NKT-2152 an "ideal candidate for combination with antibody-based regimens" [1], as many therapeutic antibodies also possess long half-lives, allowing for synchronized drug exposure.

Pharmacodynamic (PD) Effects:

Pharmacodynamic studies have provided clear evidence of NKT-2152's target engagement in humans:

• Erythropoietin (EPO) Suppression: Significant and sustained suppression of plasma EPO levels, a well-established downstream target gene of HIF2α, was observed at all dose levels of NKT2152 tested in the NCT05119335 study.[6] This serves as a robust PD biomarker, confirming that NKT-2152 effectively inhibits the HIF2α pathway in patients.
• Magnitude of EPO Suppression: The maximal fractional inhibition of EPO production (Imax) was reported to be 72% (or 0.75).[6]
• Potency of EPO Suppression: The plasma concentration of NKT2152 required for 50% maximal inhibition of EPO production (IC50 for EPO suppression) was determined to be 16.4 ng/mL [6] or 63 ng/mL.[23] Importantly, these concentrations were reportedly exceeded at all tested dose levels, indicating consistent and robust target inhibition across the dose range evaluated.[6]

Dosing Regimens and Rationale:

The unique PK profile, particularly the long half-life, has driven the exploration of various dosing regimens:

• The Phase 1 component of the NCT05119335 study in ccRCC evaluated four daily dosing cohorts and four distinct loading/maintenance dose regimens. Examples of loading/maintenance schedules included 200 mg of NKT2152 administered once daily for 7, 14, or 28 days, followed by lower daily maintenance doses (e.g., 50 mg QD) or less frequent maintenance doses (e.g., 200 mg weekly).[6]
• The observed PK/PD profiles, showing sustained target engagement (EPO suppression) with these regimens, support the rationale for such loading and maintenance dosing strategies.[6] This approach aims to rapidly achieve therapeutic drug concentrations with the loading dose and then maintain these levels effectively with a more convenient or better-tolerated maintenance schedule.

6. Safety and Tolerability Profile of NKT-2152

The safety and tolerability of NKT-2152 have been evaluated in ongoing clinical trials, primarily through the NCT05119335 study in patients with advanced ccRCC.

Overall Assessment:

NKT-2152 has generally demonstrated a manageable and favorable safety profile. The observed adverse events (AEs) are largely consistent with the known on-target effects stemming from the inhibition of the HIF2α pathway.1

Common Adverse Events (AEs) from NCT05119335 (ccRCC, monotherapy):

Data from approximately 100-113 patients in the NCT05119335 study indicate that the most frequently reported treatment-emergent AEs (TEAEs, any grade, occurring in ≥10% of patients) include 6:

• Anemia: This is a very common, expected on-target effect resulting from the NKT-2152-mediated suppression of erythropoietin (EPO). Incidence rates reported vary slightly across sources, from approximately 71% [7] to around 92% [6] of patients experiencing any grade of anemia. This predictability allows for anticipatory monitoring and management, such as regular hemoglobin checks and, if necessary, interventions like blood transfusions or the use of erythropoiesis-stimulating agents (though the latter might counteract the drug's PD effect on EPO).
• Fatigue: A frequently reported AE.
• Hypoxia: Also considered an on-target AE related to HIF2α's role in oxygen sensing and homeostasis.
• Nausea
• Dizziness
• Peripheral Edema
• Dyspnea (shortness of breath)

Table 4: Summary of Common Treatment-Emergent Adverse Events (TEAEs ≥10%) with NKT-2152 Monotherapy in NCT05119335 (ccRCC)

Adverse Event (MedDRA Term)	Any Grade Frequency (%)	Grade ≥3 Frequency (%)	Notes	Snippet ID(s)
Anemia	~71% - 92%	N/A in specific snippets for Grade ≥3 frequency	On-target effect (EPO suppression)	6
Fatigue	≥10% (specific % N/A)	N/A in specific snippets for Grade ≥3 frequency		6
Hypoxia	≥10% (specific % N/A)	N/A in specific snippets for Grade ≥3 frequency	On-target effect	6
Nausea	≥10% (specific % N/A)	N/A in specific snippets for Grade ≥3 frequency		6
Dizziness	≥10% (specific % N/A)	N/A in specific snippets for Grade ≥3 frequency		6
Peripheral Edema	≥10% (specific % N/A)	N/A in specific snippets for Grade ≥3 frequency		6
Dyspnea	≥10% (specific % N/A)	N/A in specific snippets for Grade ≥3 frequency		6

N/A: Not available in the specific snippets for this level of detail.

Serious Adverse Events (SAEs) and Discontinuations:

In the NCT05119335 study cohort of 96 patients (data cut-off Feb 2024), 14% of patients discontinued NKT-2152 treatment due to an adverse event.23

Dose-Limiting Toxicities (DLTs):

During the dose-escalation phase of NCT05119335, DLTs were observed in some of the loading/maintenance dose cohorts. These DLTs primarily consisted of fatigue and hypoxia.6

• Specifically, in a cohort receiving NKT2152 200 mg daily for 14 days followed by 50 mg daily, 1 out of 12 patients experienced DLTs (fatigue and hypoxia).
• In a cohort receiving NKT2152 200 mg daily for 28 days followed by 50 mg daily, 1 out of 9 patients experienced DLTs (fatigue and hypoxia). Despite these DLTs, the Maximum Tolerated Dose (MTD) was reportedly not reached in the dose-escalation phase according to the ESMO 2024 abstract presentation.[4] The occurrence of these on-target DLTs, particularly with regimens involving higher initial exposure due to loading doses, underscores the importance of carefully selecting the dose and schedule. The long half-life of NKT-2152 implies that if such toxicities develop, they might be prolonged, necessitating strategies that balance achieving therapeutic concentrations rapidly with maintaining long-term tolerability.

No specific contraindications or black box warnings for NKT-2152 were identified in the provided research material. Information in snippets [32] and [33] pertains to other pharmaceutical agents.

7. Regulatory Status and Future Perspectives

Current Regulatory Standing:

NKT-2152 is an investigational drug currently advancing through Phase 1 and Phase 2 clinical development across multiple indications.1 As of the information available, it has not yet received marketing approval from major regulatory authorities such as the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA). The provided documentation does not contain information regarding any specific regulatory designations for NKT-2152 itself, such as Fast Track, Breakthrough Therapy, or Orphan Drug Designation, from these agencies. While such designations are often sought for promising drugs in areas of unmet need, information on this aspect for NKT-2152 was not present in the reviewed materials.8

Anticipated Future Development and Milestones:

The clinical development of NKT-2152 is ongoing and expected to progress through several key stages:

• Continued Data Accrual and Analysis: Further patient enrollment and follow-up in the active Phase 2 trials, including the ccRCC combination study (NCT05935748) and the NKT-2152 arm of the MORPHEUS-Liver trial for HCC (NCT04524871), will be critical.
• Reporting of Mature Data: Future disclosures are anticipated to include more mature data from these studies, focusing on long-term efficacy outcomes such as overall survival (OS) and duration of response (DOR), as well as comprehensive long-term safety data.
• Pivotal Trials: Should the Phase 2 data demonstrate a compelling risk-benefit profile and substantial clinical activity, the initiation of pivotal Phase 3 trials would be the logical next step towards seeking regulatory approval.
• Expansion into Other Indications: Based on the broad preclinical anti-tumor activity and the underlying scientific rationale for HIF2α inhibition in various cancers, NiKang Therapeutics and its collaborators may explore NKT-2152 in additional solid tumor types beyond ccRCC and HCC.[1]
• Optimization of Treatment Regimens: Ongoing research will likely continue to focus on defining the optimal dosing strategies for NKT-2152, both as monotherapy and as part of combination regimens, and identifying the most suitable patient populations and combination partners.[7]

NKT-2152 is evidently a cornerstone asset within NiKang Therapeutics' oncology pipeline, as suggested by the numerous press releases and active clinical trial programs.[1] The strategic collaborations with major pharmaceutical entities like Roche, Pfizer, and AVEO Oncology are pivotal. These partnerships provide not only financial resources and access to complementary therapeutic agents for combination studies but also crucial expertise in clinical trial execution and navigating complex regulatory pathways in specific tumor types.[1] Such collaborations significantly enhance the scope and potential pace of NKT-2152's overall development program. The current stage of development, with multiple Phase 1/2 studies actively generating data, places NKT-2152 at a critical juncture where robust proof-of-concept in various therapeutic settings is being established, which will inform future pivotal development and regulatory strategies.

8. Key Insights and Concluding Remarks

NKT-2152 has emerged as a significant investigational agent in the landscape of targeted oncology therapies. Its development is characterized by a strong scientific rationale, a unique pharmacological profile, and a comprehensive clinical evaluation program.

Synthesis of Critical Findings:

NKT-2152 is an orally bioavailable, selective allosteric inhibitor of HIF2α. This mechanism of action is particularly relevant for VHL-mutant ccRCC but also holds promise for other malignancies where HIF2α signaling contributes to tumor progression.1 Preclinical studies have substantiated its anti-tumor activity across various models.1

In the clinical setting, NKT-2152 monotherapy has demonstrated meaningful efficacy in a heavily pretreated advanced ccRCC patient population (NCT05119335), with reported objective response rates in the range of 20-26.3% and a median progression-free survival of approximately 7-9 months.[5] A key differentiator for NKT-2152 is its distinct pharmacokinetic profile, notably a long terminal half-life of around 38 days. This characteristic supports sustained target engagement, as evidenced by consistent EPO suppression, and allows for the exploration of potentially more convenient loading and maintenance dosing regimens.[1] The safety profile of NKT-2152 has been generally manageable and aligns with the known class effects of HIF2α inhibitors, with anemia and hypoxia being the most common on-target adverse events. Careful optimization of dose and schedule is crucial, especially considering the drug's prolonged half-life.[5]

Assessment of Potential Positioning and Competitive Landscape:

NKT-2152 is positioned to potentially offer a new therapeutic option for patients with advanced ccRCC who have progressed on prior therapies. Its unique PK/PD characteristics may provide differentiation from other HIF2α inhibitors, such as belzutifan, if these translate into improved clinical outcomes, such as enhanced durability of response, better tolerability with optimized schedules, or greater convenience for patients. The extensive clinical development strategy, which heavily emphasizes combination therapies (e.g., with VEGFR TKIs like tivozanib, CDK4/6 inhibitors like palbociclib, and immunotherapies like atezolizumab/sasanlimab) across both ccRCC and HCC, suggests an ambition to establish NKT-2152 as a versatile agent, either as a backbone therapy or a key combination partner in various oncologic settings.1

Unanswered Questions and Future Directions:

Several critical questions remain to be addressed as the development of NKT-2152 continues:

• Long-Term Outcomes: Mature data on overall survival and long-term duration of response from ongoing and future trials are essential to fully define its clinical benefit.
• Comparative Efficacy: Head-to-head comparisons or robust contextualization against existing standards of care, including other HIF2α inhibitors, will be necessary in later-phase trials.
• Biomarker Development: The identification and validation of predictive biomarkers could help select patient populations most likely to benefit from NKT-2152, optimizing its therapeutic application.
• Management of Long-Term Toxicities: Given its long half-life, understanding and managing potential cumulative or delayed on-target toxicities with prolonged exposure will be important.
• Combination Regimen Optimization: The outcomes of the various ongoing combination studies will be pivotal in defining the optimal partners, sequences, and dosing schedules for NKT-2152 in different indications.

Overall Conclusion:

NKT-2152 is a promising, orally administered HIF2α inhibitor characterized by a distinct pharmacokinetic profile and demonstrated clinical activity, particularly in advanced ccRCC. Its comprehensive development program, which includes monotherapy and diverse combination strategies across multiple tumor types like HCC, supported by significant strategic collaborations, positions NKT-2152 as an important investigational compound in the oncology pipeline. Continued positive and mature data from its ongoing and planned clinical trials will be crucial in determining its ultimate role and path toward becoming a new therapeutic option for patients with challenging malignancies.

The development of NKT-2152, especially its foray into HCC and its use in varied combination regimens, highlights an expanding appreciation of the HIF2α pathway's therapeutic relevance beyond traditionally VHL-mutated cancers. Should NKT-2152 achieve success, particularly in broader indications or with differentiated clinical benefits attributable to its unique pharmacological properties, it could significantly influence the therapeutic landscape for HIF2α inhibitors as a class. Furthermore, the clinical experience gained in managing an oral oncology agent with such a prolonged half-life will offer valuable insights for the development and administration of future therapeutics with similar pharmacokinetic challenges and opportunities.

Works cited

1. NiKang Therapeutics® Announces First Patient Dosed in a Phase ..., accessed May 20, 2025, https://www.businesswire.com/news/home/20250121611640/en/NiKang-Therapeutics-Announces-First-Patient-Dosed-in-a-Phase-1b2-Study-of-NKT2152-in-Combination-with-Standard-of-Care-in-First-Line-Regimen-for-Hepatocellular-Carcinoma
2. NiKang Therapeutics® Announces First Patient Dosed in a Phase 1b/2 Study of NKT2152 in Combination with Standard-of-Care in First-Line Regimen for Hepatocellular Carcinoma - BioSpace, accessed May 20, 2025, https://www.biospace.com/press-releases/nikang-therapeutics-announces-first-patient-dosed-in-a-phase-1b-2-study-of-nkt2152-in-combination-with-standard-of-care-in-first-line-regimen-for-hepatocellular-carcinoma
3. NiKang Therapeutics, Inc. - Drug pipelines, Patents, Clinical trials - Patsnap Synapse, accessed May 20, 2025, https://synapse.patsnap.com/organization/eaf2644c4babaa88c923240ce07ebd7d
4. NKT-2152 Drug Profile - Ozmosi, accessed May 20, 2025, https://pryzm.ozmosi.com/product/24792
5. NKT2152 Ushers in a New Era of HIF-2α Inhibition in Pretreated Advanced ccRCC, accessed May 20, 2025, https://www.onclive.com/view/nkt2152-ushers-in-a-new-era-of-hif-2-inhibition-in-pretreated-advanced-ccrcc
6. Promising Results from Phase 1/2 Trial of NKT2152 for Advanced Kidney Cancer, accessed May 20, 2025, https://www.targetedonc.com/view/promising-results-from-phase-1-2-trial-of-nkt2152-for-advanced-kidney-cancer
7. NKT2152 Generates Responses in Heavily Pretreated Advanced ..., accessed May 20, 2025, https://www.onclive.com/view/nkt2152-generates-responses-in-heavily-pretreated-advanced-ccrcc
8. NKT-2152: A Promising HIF-2α Inhibitor in ccRCC - Targeted Oncology, accessed May 20, 2025, https://www.targetedonc.com/view/nkt-2152-a-promising-hif-2-inhibitor-in-ccrcc
9. A Phase I Dose-Escalation Study of the HIF-2 Alpha Inhibitor DFF332 in Patients with Advanced Clear-Cell Renal Cell Carcinoma - PMC - PubMed Central, accessed May 20, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC12079095/
10. HIF-2α Inhibitors Make Significant Inroads in Renal Cell Carcinoma - Targeted Oncology, accessed May 20, 2025, https://www.targetedonc.com/view/hif-2-inhibitors-make-significant-inroads-in-renal-cell-carcinoma
11. UCSF Liver Cancer Trial → Multiple Immunotherapy-Based Treatment Combinations in Patients With Advanced Liver Cancers (Morpheus-Liver) - UCSF Clinical Trials, accessed May 20, 2025, https://clinicaltrials.ucsf.edu/trial/NCT04524871
12. Amezalpat Receives FDA Fast Track Designation for Hepatocellular Carcinoma - Oncology Nursing News, accessed May 20, 2025, https://www.oncnursingnews.com/view/amezalpat-receives-fda-fast-track-designation-for-hepatocellular-carcinoma
13. FDA Fast Tracks Amezalpat for HCC Treatment - Targeted Oncology, accessed May 20, 2025, https://www.targetedonc.com/view/fda-fast-tracks-amezalpat-for-hcc-treatment
14. Dr Choueiri on Initial Efficacy Data With NKT2152 in Pretreated ccRCC - OncLive, accessed May 20, 2025, https://www.onclive.com/view/dr-choueiri-on-initial-efficacy-data-with-nkt2152-in-pretreated-ccrcc
15. News – Nikang Therapeutics, accessed May 20, 2025, https://www.nikangtx.com/news/
16. NiKang Therapeutics Presents Preclinical Data Highlighting NKT2152's Therapeutic Potential in Clear Cell Renal Cell Carcinoma (ccRCC) and Solid Tumors Beyond ccRCC at AACR Annual Meeting 2022 - BioSpace, accessed May 20, 2025, https://www.biospace.com/nikang-therapeutics-presents-preclinical-data-highlighting-nkt2152-s-therapeutic-potential-in-clear-cell-renal-cell-carcinoma-ccrcc-and-solid-tumors-beyond-ccrcc-at-aacr-annual-meeting-2022
17. NiKang Therapeutics® Announces First Patient Dosed in a Phase 1b/2 Study of NKT2152 in Combination with Standard-of-Care in First-Line Regimen for Hepatocellular Carcinoma | Business Wire, accessed May 20, 2025, https://www.businesswire.com/news/home/20250121611640/en/NiKang-Therapeutics%C2%AE-Announces-First-Patient-Dosed-in-a-Phase-1b2-Study-of-NKT2152-in-Combination-with-Standard-of-Care-in-First-Line-Regimen-for-Hepatocellular-Carcinoma
18. NiKang Therapeutics and AVEO Oncology Announce a Clinical Trial Collaboration and Supply Agreement to Evaluate the Combination of NKT2152, a HIF2α Inhibitor, and FOTIVDA® (tivozanib) for the Treatment of Advanced Clear Cell Renal Cell Carcinoma, accessed May 20, 2025, https://www.aveooncology.com/nikang-therapeutics-and-aveo-oncology-announce-a-clinical-trial-collaboration-and-supply-agreement-to-evaluate-the-combination-of-nkt2152-a-hif2%CE%B1-inhibitor-and-fotivda-tivozanib-for-the/
19. The Targeted Pulse: NKT2152 Sparks Excitement in RCC, Amivantamab/Chemotherapy Combo Receives Approval for EGFR-Mutant NSCLC, and More, accessed May 20, 2025, https://www.targetedonc.com/view/targeted-pulse-september-29
20. Dr Jonasch on the Preliminary Efficacy of NKT-2152 in Advanced ccRCC - OncLive, accessed May 20, 2025, https://www.onclive.com/view/dr-jonasch-on-the-preliminary-efficacy-of-nkt-2152-in-advanced-ccrcc
21. NKT2152 Data Reinforce the Importance of HIF2α Inhibition in Advanced Clear Cell RCC, accessed May 20, 2025, https://www.onclive.com/view/nkt2152-data-reinforce-the-importance-of-hif2-inhibition-in-advanced-clear-cell-rcc
22. A Study of NKT2152, a HIF2a Inhibitor, in Patients With Advanced Clear Cell Renal Cell Carcinoma, accessed May 20, 2025, https://www.georgiacancerinfo.org/trialDetailPrint.aspx?trialID=5238
23. 1690O NKT2152, a novel oral HIF-2α inhibitor, in participants (pts ..., accessed May 20, 2025, https://iro.uiowa.edu/esploro/outputs/abstract/1690O-NKT2152-a-novel-oral-HIF-2%CE%B1/9984708955302771
24. clinicaltrials.gov, accessed May 20, 2025, https://clinicaltrials.gov/study/NCT05119335
25. A Study of NKT2152, a HIF2α Inhibitor, in Patients with Advanced Clear Cell Renal Cell Carcinoma | Clinical Research Trial Listing - CenterWatch, accessed May 20, 2025, https://www.centerwatch.com/clinical-trials/listings/NCT05119335/a-study-of-nkt2152-a-hif2a-inhibitor-in-patients-with-advanced-clear-cell-renal-cell-carcinoma
26. Ph2 Study NKT2152 with Palbociclib & Sasanlimab in Subjects with Advanced Clear Cell Renal Cell Carcinoma (ccRcc) - National Cancer Institute, accessed May 20, 2025, https://www.cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2023-06504
27. Recommended Tips for Creating an Orphan Drug Designation Application - FDA, accessed May 20, 2025, https://www.fda.gov/media/111762/download
28. Rilzabrutinib granted orphan drug designation in the US for two rare diseases with no approved medicines - Sanofi US News, accessed May 20, 2025, https://www.news.sanofi.us/2025-04-03-Rilzabrutinib-granted-orphan-drug-designation-in-the-US-for-two-rare-diseases-with-no-approved-medicines
29. Oncology Drugs Fast-Tracked by the FDA in February 2025, accessed May 20, 2025, https://www.oncologynewscentral.com/drug/oncology-drugs-fast-tracked-by-the-fda-in-february-2025
30. Fruquintinib/Sintilimab Generates Favorable PFS Outcomes in Advanced RCC - OncLive, accessed May 20, 2025, http://www.onclive.com/view/fruquintinib-sintilimab-generates-favorable-pfs-outcomes-in-advanced-rcc
31. Emerging innovative treatment strategies for advanced clear cell renal cell carcinoma - PMC, accessed May 20, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11954509/
32. Pemoline: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed May 20, 2025, https://go.drugbank.com/drugs/DB01230
33. FDA Approval Sought for Enfortumab Vedotin for Urothelial Cancer - OncLive, accessed May 20, 2025, https://www.onclive.com/view/fda-approval-sought-for-enfortumab-vedotin-for-urothelial-cancer