What HIF-2α inhibitors are in clinical trials currently?

Introduction to HIF-2α

Hypoxia-inducible factor 2α (HIF-2α) is a transcription factor that plays a pivotal role in oxygen homeostasis by regulating the expression of genes involved in angiogenesis, metabolism, cell proliferation, and survival. Under normoxic conditions, HIF-2α is hydroxylated by prolyl hydroxylase domain (PHD) enzymes, leading to its recognition by the von Hippel-Lindau (VHL) protein and subsequent degradation. Under hypoxic conditions, however, HIF-2α is stabilized and translocates to the nucleus, where it dimerizes with HIF-1β and binds to hypoxia response elements (HREs) in target gene promoters.

Role in Physiology and Pathology

Physiologically, HIF-2α is essential for developmental processes, erythropoiesis, and maintaining vascular integrity. In pathology, especially in tumor environments, chronic or fluctuating hypoxia leads to its stabilization, which in turn results in angiogenesis, metabolic reprogramming, and ultimately, tumor progression. HIF-2α is known to drive the expression of vascular endothelial growth factor (VEGF) and other pro-angiogenic factors in multiple malignancies, including renal cell carcinoma (RCC), hepatocellular carcinoma, and certain neuroendocrine tumors. Furthermore, its unique spatial and temporal expression—as opposed to HIF-1α—often makes it a more viable target in settings where selective inhibition of hypoxic responses is desirable.

Importance as a Drug Target

Given its critical role in the adaptation of tumor cells to hypoxic stress and its function in driving oncogenesis in several cancers, HIF-2α is recognized as a compelling drug target. Inhibition of HIF-2α has the potential to attenuate pro-angiogenic signaling and reduce tumor cell survival under hypoxic conditions without interfering with normal tissue functions that are less reliant on hypoxic signaling. As a result, significant research efforts have been directed toward the discovery and clinical development of small-molecule HIF-2α inhibitors that promise to offer improved therapeutic outcomes with a more favorable safety profile.

Current HIF-2α Inhibitors in Clinical Trials

Research and clinical development have led to the identification of several HIF-2α inhibitors that are being evaluated in various phases of clinical trials. Among these, belzutifan (MK-6482) has emerged as the most widely studied agent, although other novel compounds, including AB521, BPI-452080, NKT2152, and combination regimens with emerging agents like Zanzalintinib (XL092), are also in various stages of clinical assessment.

List of Inhibitors

1. Belzutifan (MK-6482/PT2977):
Belzutifan is a small-molecule HIF-2α inhibitor that has been extensively investigated in clinical trials. It was designed to bind to a ligandable pocket within the PAS-B domain of HIF-2α, thereby preventing its dimerization with HIF-1β and subsequent transcription of hypoxia-responsive genes. Belzutifan is currently studied in a range of indications including advanced clear cell renal cell carcinoma (ccRCC), von Hippel–Lindau (VHL) disease–associated tumors, pancreatic neuroendocrine tumors (pNET), pheochromocytoma/paraganglioma (PPGL), and even recurrent clear cell ovarian carcinoma.

2. AB521:
AB521 is a novel small-molecule inhibitor that is primarily evaluated in early-phase clinical trials for its safety, tolerability, and pharmacokinetic (PK) profile. It is designed to inhibit HIF-2α activity in clear cell renal cell carcinoma and other solid tumor indications. AB521 is under a Phase 1 investigation, with additional PK and relative bioavailability studies to determine its optimal formulation.

3. BPI-452080:
BPI-452080 is in early clinical development as a Phase 1 inhibitor targeting HIF-2α in patients with various solid tumors. Preliminary clinical data are focused on evaluating its safety and tolerability, as well as exploring its pharmacokinetic characteristics.

4. NKT2152:
NKT2152 is being evaluated in a Phase 2 clinical trial as part of combination regimens. In this study, NKT2152 is administered either as a doublet with palbociclib or as a triplet combining palbociclib and sasanlimab in subjects with advanced or metastatic clear cell renal cell carcinoma.

5. Zanzalintinib (XL092) in Combination with AB521:
Zanzalintinib (XL092) is being studied as part of combination therapy regimens alongside AB521 – either with AB521 alone or in conjunction with AB521 plus nivolumab. These investigations target patients with advanced clear cell renal cell carcinoma or other advanced solid tumors, aiming to explore synergistic effects that may overcome resistance mechanisms.

6. Additional Combination Studies Involving Belzutifan:
Several trials are exploring belzutifan in combination with other therapeutic agents. For example, belzutifan is being investigated in combination with pembrolizumab in a Phase III study as an adjuvant therapy following nephrectomy in ccRCC patients. Other combinations include belzutifan with palbociclib versus belzutifan monotherapy for advanced renal cell carcinoma and belzutifan combined with HC-7366 for patients with locally advanced or metastatic RCC. Furthermore, a post-authorization safety (PAS) study is being conducted to further characterize belzutifan’s safety in patients with VHL-associated conditions.

7. Single Dose Studies and Pharmacokinetic Assessments:
In addition to efficacy studies, belzutifan has been evaluated in single-dose clinical studies, such as in healthy Japanese female participants, to assess its pharmacokinetic properties. Such studies are critical for determining dose proportionality, absorption, and distribution characteristics necessary for optimizing therapeutic regimens.

Clinical Trial Phases and Results

The clinical development of HIF-2α inhibitors spans multiple phases:

– Belzutifan (MK-6482):
Belzutifan has progressed through several phases of clinical evaluation. In early-phase studies, belzutifan demonstrated a favorable safety profile with manageable side effects such as anemia and hypoxia-related symptoms. In a Phase I trial, belzutifan achieved a disease control rate of around 80% in pretreated ccRCC, setting a strong foundation for its further development. Subsequent Phase II trials continued to report strong efficacy signals in various HIF-2α–driven tumor types. Moreover, Phase III studies are currently evaluating belzutifan in combination regimens. For instance, a Phase III trial is underway to assess belzutifan plus pembrolizumab versus placebo plus pembrolizumab as adjuvant therapy following nephrectomy in ccRCC. Additionally, a Phase II study evaluating belzutifan across several indications including PPGL, pNET, VHL disease–associated tumors, and advanced solid tumors further supports its broad clinical potential. In the post-authorization setting, a non-interventional safety study (PAS) is being conducted to gather additional real-world evidence on belzutifan’s safety profile in VHL-associated RCC and other tumors.

– AB521:
AB521 is in early-phase clinical development (Phase 1), focusing on determining its maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetic profile in patients with solid tumors, including ccRCC. A separate relative bioavailability study (Phase 1, open-label, randomized crossover design) of AB521 tablet versus capsule formulations, as well as the effect of food on absorption, has been performed to optimize its formulation and dosing.

– BPI-452080:
The Phase 1 study of BPI-452080 has recently been initiated to evaluate its safety, tolerability, and pharmacokinetics in patients with solid tumors. Early clinical results will help determine its efficacy as well as inform subsequent Phase 1b/2 studies focusing on dose expansion and preliminary antitumor activity.

– NKT2152:
NKT2152 has advanced into a Phase 2 state where its safety and efficacy are being examined in combination with palbociclib and sasanlimab. The rationale behind this combination is to synergistically target multiple pathways involved in tumor progression, with the hypothesis that dual or triplet inhibition may overcome compensatory mechanisms that lead to resistance.

– Zanzalintinib (XL092) + AB521 Combination:
This combination study is designed as a Phase 1b/2 dose-finding and expansion trial to determine the optimal dosing regimen of Zanzalintinib combined with AB521, with or without nivolumab, in patients with advanced clear cell RCC or other solid tumors. The goal is to assess the synergistic safety and efficacy of these combinations, exploring whether this strategy can provide enhanced antitumor activity compared to monotherapy.

– Combination Studies Involving Belzutifan:
Several combination trials with belzutifan are ongoing. One notable trial is a Phase III double-blind, placebo-controlled study that examines belzutifan plus pembrolizumab versus placebo plus pembrolizumab in the adjuvant setting post-nephrectomy for ccRCC. Another trial is examining belzutifan in combination with palbociclib versus belzutifan monotherapy in patients with advanced RCC to evaluate the added benefit of cell-cycle inhibition. Furthermore, a Phase 1b study evaluates the safety, tolerability, and preliminary efficacy of HC-7366 in combination with belzutifan in patients with locally advanced or metastatic RCC.

Collectively, these trials represent a multi-faceted clinical evaluation of HIF-2α inhibition across various tumor types and treatment regimens. Their results are providing insight not only into the efficacy of HIF-2α inhibitors alone but also into how best to combine them with other therapeutic modalities to improve patient outcomes.

Therapeutic Applications of HIF-2α Inhibitors

HIF-2α inhibitors are primarily being pursued for their promise in the treatment of cancers that are driven by hypoxic signaling. However, their therapeutic applications extend beyond monotherapy, with significant potential in both combination treatments and in other disease areas related to iron metabolism and potential hypoxia-induced disturbances.

Cancer Treatments

– Renal Cell Carcinoma (RCC):
The most advanced clinical application of HIF-2α inhibition is in clear cell renal cell carcinoma (ccRCC). Given that loss of VHL function in ccRCC often leads to constitutive stabilization of HIF-2α, inhibitors like belzutifan have been developed specifically for this indication. Trials have shown that belzutifan has a meaningful disease control rate in ccRCC patients and is being tested as both standalone and combination therapy after surgical procedures such as nephrectomy. The combination of HIF-2α inhibition with agents such as pembrolizumab or palbociclib is particularly promising to address resistance mechanisms.

– Von Hippel–Lindau (VHL) Disease–Associated Tumors:
VHL disease results in a predisposition to various tumors, including hemangioblastomas, pancreatic lesions, and RCC. Belzutifan has been approved for use in this context and is under continuous evaluation in Phase II trials focused on patients with VHL-associated tumors, where its impact on reducing tumor burden and controlling disease progression is rigorously assessed.

– Neuroendocrine Tumors (pNET and PPGL):
Clinical trials are evaluating belzutifan in the treatment of pancreatic neuroendocrine tumors and pheochromocytoma/paraganglioma. In these Phase II trials, the aim is to determine the efficacy and tolerability of HIF-2α inhibition in reducing tumor growth in neuroendocrine malignancies driven by aberrant hypoxic signaling.

– Other Solid Tumors:
Beyond RCC and VHL disease–associated tumors, HIF-2α inhibitors are being evaluated in a broader spectrum of solid tumors. For example, early-phase trials for BPI-452080 and AB521 include subjects with various advanced solid tumors. The strategy in these trials is to assess whether targeting HIF-2α can overcome the hypoxic and resistant microenvironment present in many solid tumors. Combinatorial studies, such as those involving Zanzalintinib and NKT2152, broaden the application of HIF-2α inhibitors to other cancers that are heavily reliant on hypoxia-driven survival pathways.

Other Potential Indications

– Iron Overload Disorders:
Some patents and early research have suggested that HIF-2α inhibitors may have applications beyond oncology. For instance, specific HIF-2α inhibitors are being investigated for the treatment of iron overload disorders, where modulation of the HIF pathway could help rebalance iron homeostasis. Although the main focus remains on cancer, these studies highlight the versatility of HIF-2α as a target in conditions where aberrant iron metabolism is a concern.

– Combination with Other Drug Classes:
The integration of HIF-2α inhibitors with other therapeutic agents, such as PARP inhibitors—as noted in some patents—and with other targeted kinase inhibitors, exemplifies the potential of these agents to be used in combination regimens outside pure monotherapy scenarios. Such approaches are actively being tested in clinical trials, where the aim is to potentiate the overall antitumor effect while minimizing resistance and toxicity.

Challenges and Future Directions in HIF-2α Inhibitor Development

Despite the promising clinical activity shown by HIF-2α inhibitors, several challenges and avenues for future research remain. Addressing these challenges is critical to fully harnessing the potential of HIF-2α–targeted therapies in oncology and beyond.

Current Challenges

– Selectivity and Off-Target Effects:
While the design of inhibitors such as belzutifan has focused on the ligandable pocket in the HIF-2α PAS-B domain to ensure specificity, off-target effects remain a concern. Given that many proteins contain similar PAS domains, there is the potential for unexpected interactions which could lead to off-target toxicity. This challenge is compounded by the fact that HIF-2α plays crucial roles even in normal physiology. Thus, achieving an optimal balance between potent inhibition of pathological HIF-2α signaling and preservation of normal function is a major focus.

– Adverse Event Management:
Clinical trials with belzutifan have reported adverse events including anemia and hypoxia-related symptoms, which reflect the physiological roles of HIF-2α in erythropoiesis and oxygen sensing. Managing these on-target side effects without compromising efficacy is essential for the wider application of HIF-2α inhibitors. Furthermore, combination regimens, such as those adding palbociclib or pembrolizumab, require careful evaluation of drug-drug interactions and cumulative toxicity.

– Patient Selection and Biomarkers:
Identifying the appropriate patient population is imperative for the success of clinical trials with HIF-2α inhibitors. Biomarkers that predict responsiveness, such as VHL mutation status and the degree of tumor hypoxia, are under investigation. However, reliable and clinically validated biomarkers remain limited, and this gap may hinder effective treatment stratification. The development of companion diagnostics is therefore a critical area for future research.

– Resistance Mechanisms:
As with many targeted therapies, tumor cells can develop adaptive resistance to HIF-2α inhibitors. Mechanisms of resistance may include compensatory upregulation of alternative hypoxia-inducible pathways, mutations in the HIF-2α protein that reduce inhibitor binding, or activation of parallel oncogenic pathways. Understanding and overcoming these resistance mechanisms through combination therapies or next-generation inhibitors remains a challenge.

– Optimization of Drug Formulation and Pharmacokinetics:
For novel agents like AB521 and BPI-452080, ensuring optimal drug formulations—such as assessing the relative bioavailability of tablets versus capsules and understanding the impact of food effects—is essential. These pharmacokinetic considerations play a crucial role in achieving consistent plasma levels and therapeutic efficacy in diverse patient populations.

Future Research and Development Directions

– Next-Generation Inhibitors and Dual Targeting Strategies:
Future research is likely to focus on the development of dual inhibitors that can simultaneously target HIF-2α and its compensation pathways, such as HIF-1α, in order to minimize redundancy in hypoxic signaling and overcome resistance. Several studies have outlined strategies for developing dual HIF-1α/HIF-2α inhibitors or combination regimens that block complementary signaling pathways.

– Combination Therapies:
In view of the complex and multifactorial nature of tumor growth and the tumor microenvironment, future studies will likely explore a multitude of combination regimens. Combining HIF-2α inhibitors with immunotherapies (e.g., pembrolizumab, nivolumab), cell cycle inhibitors (e.g., palbociclib), or other novel agents (e.g., NKT2152, Zanzalintinib) may prove to be a powerful strategy for synergistically inhibiting tumor survival while mitigating the onset of resistance.

– Development of Predictive Biomarkers and Companion Diagnostics:
To facilitate patient selection and monitor therapeutic response, rigorous biomarker development is essential. Future translational research will focus on identifying and validating biomarkers linked to HIF-2α pathway activity, which could include molecular signatures from tumor biopsies or circulating markers measured in liquid biopsies. These companion diagnostics will support the personalization of therapy and enhance clinical trial design.

– Innovative Trial Designs:
Novel statistical designs and adaptive clinical trial methodologies will be increasingly employed to streamline the evaluation of HIF-2α inhibitors. Given the rapidly changing landscape of targeted cancer therapies, future trials may incorporate basket or umbrella designs that allow for the simultaneous evaluation of multiple inhibitors or combinations in molecularly defined subgroups, expediting the development process and improving therapeutic outcomes.

– Exploration Beyond Oncology:
While the focus of HIF-2α inhibitors has primarily been on oncology, emerging evidence suggests potential applications in non-cancer indications, such as iron overload disorders. Future research exploring the modulation of iron metabolism through HIF-2α inhibition could open new therapeutic avenues, expanding the impact of these agents beyond the realm of cancer.

– Long-Term Safety and Real-World Effectiveness:
Continued monitoring through post-authorization safety (PAS) studies, like the one currently underway for belzutifan, will provide important insights into the long-term safety profile of HIF-2α inhibitors. Such studies are crucial for understanding chronic toxicities and optimizing treatment regimens across broader patient populations.

Conclusion

In summary, the current landscape of HIF-2α inhibitors in clinical trials is both dynamic and multifaceted. Belzutifan (MK-6482), arguably the flagship molecule in this class, has demonstrated significant efficacy in various Phase I, II, and III trials across multiple indications such as ccRCC, VHL-associated tumors, pNET, and PPGL, with additional studies evaluating its role in combination therapies and in diverse patient populations, including healthy Japanese cohorts. Other innovative compounds like AB521, BPI-452080, NKT2152, and combination regimens involving Zanzalintinib (XL092) are in early clinical development, offering insight into potential therapeutic synergisms that may overcome intrinsic tumor resistance mechanisms.

Furthermore, while the primary focus remains on the management of various cancers through precise HIF-2α inhibition, emerging studies also extend this therapeutic strategy to other disease areas, such as iron overload disorders, thereby broadening the scope of potential applications. However, challenges including off-target effects, management of adverse events, identification of robust predictive biomarkers, resistance mechanisms, and formulation optimization persist. Future directions will likely incorporate next-generation inhibitors, dual-targeting strategies, innovative trial designs, and the integration of comprehensive biomarker diagnostics to better stratify patients and maximize therapeutic outcomes.

Overall, the development of HIF-2α inhibitors is progressing rapidly with promising preliminary results that not only validate HIF-2α as a critical drug target but also underscore the importance of combination therapeutic approaches. Continued research efforts, improved patient selection through companion diagnostics, and adaptive clinical trial methodologies will be key to advancing these agents from promising early-phase studies to established standards of care in personalized cancer therapy. The success of these efforts could dramatically transform the management of hypoxia-driven cancers and potentially other conditions where aberrant HIF-2α signaling plays a central role.