HIF-117 (SSS17): A Comprehensive Analysis of a Novel HIF Prolyl Hydroxylase Inhibitor

Section 1: Executive Summary

This report provides a comprehensive analysis of HIF-117, an investigational small-molecule drug also identified by the development code SSS17. HIF-117 is an orally administered Hypoxia-Inducible Factor Prolyl Hydroxylase (HIF-PH) inhibitor developed by the Chinese biopharmaceutical company 3SBio Inc., through its subsidiary Shenyang Sunshine Pharmaceutical. The primary therapeutic indication for HIF-117 is the treatment of anemia associated with Chronic Kidney Disease (CKD), a common and serious complication of renal impairment.

The mechanism of action of HIF-117 is centered on the inhibition of PHD enzymes, which are key regulators of the body's natural response to changes in oxygen availability. By inhibiting these enzymes, HIF-117 stabilizes Hypoxia-Inducible Factor-alpha (HIF-α), a transcription factor that is normally degraded in the presence of oxygen. This stabilization mimics a physiological state of hypoxia, leading to a coordinated upregulation of genes involved in erythropoiesis. The principal outcomes are an increase in endogenous erythropoietin (EPO) production and an improvement in iron metabolism through the suppression of hepcidin. This dual action on both red blood cell production and the iron supply chain required for hemoglobin synthesis represents a more integrated physiological approach compared to the current standard of care, injectable Erythropoiesis-Stimulating Agents (ESAs).

HIF-117 (SSS17) is currently in the early stages of clinical development, with several Phase 1 trials completed or underway in China to evaluate its safety, tolerability, and pharmacokinetic profile in healthy volunteers. Future studies, including a Phase 2 dose-finding trial in non-dialysis CKD patients, are planned. The development program follows a clear "China-first" strategy, leveraging 3SBio's established presence in the Chinese nephrology market.

The therapeutic landscape for CKD anemia is undergoing a significant transition from injectable biologics to oral small molecules. The HIF-PHI class, to which HIF-117 belongs, is highly competitive, with several agents already approved in major markets, including Roxadustat, Daprodustat, and Vadadustat. While these competitors have validated the therapeutic target and demonstrated efficacy non-inferior to ESAs, their clinical development has highlighted a significant class-wide safety concern: the potential for long-term cardiovascular risk. The divergent regulatory outcomes for these drugs, particularly in the United States, underscore that the demonstration of a clean cardiovascular safety profile in large, long-term outcome trials is the paramount hurdle for market approval and commercial success.

The primary strategic challenge for HIF-117 will be to navigate this competitive and regulatory environment. Its success will be contingent on its ability to demonstrate a competitive, if not superior, efficacy and safety profile. Specifically, its performance in future Phase 3 trials with respect to Major Adverse Cardiovascular Events (MACE) will be the ultimate determinant of its clinical utility and commercial viability on a global scale.

Section 2: The Hypoxia-Inducible Factor (HIF) Pathway: A Foundational Therapeutic Target

The therapeutic strategy underpinning HIF-117 is rooted in the modulation of the Hypoxia-Inducible Factor (HIF) pathway, a fundamental and highly conserved biological mechanism that allows cells to sense and adapt to changes in oxygen availability. The discovery of this pathway, recognized with the 2019 Nobel Prize in Physiology or Medicine, has unveiled a central regulator of cellular metabolism, survival, and vascularization, making it a target of immense therapeutic interest across multiple disease areas.[1]

2.1 Molecular Machinery of Oxygen Sensing

The core of the HIF pathway is a set of heterodimeric transcription factors. These factors are composed of an oxygen-sensitive α-subunit and a constitutively expressed β-subunit, also known as the Aryl Hydrocarbon Receptor Nuclear Translocator (ARNT).[2] There are three primary isoforms of the

α-subunit—HIF-1$\alpha$, HIF-2$\alpha$, and HIF-3$\alpha$—each with distinct, though sometimes overlapping, functions and tissue expression patterns.[1]

The regulation of this system is exquisitely sensitive to cellular oxygen levels, a process mediated by a family of enzymes known as HIF prolyl hydroxylases (PHDs, specifically PHD1, PHD2, and PHD3).[1] Under normoxic conditions, where oxygen is plentiful, these PHD enzymes act as the primary oxygen sensors. They are 2-oxoglutarate and iron (

Fe2+)-dependent dioxygenases that utilize molecular oxygen to catalyze the hydroxylation of specific proline residues located within the oxygen-dependent degradation domain (ODDD) of the HIF-α subunits.[1]

This post-translational modification is a critical step, as the hydroxylated proline residues create a high-affinity binding site for the von Hippel-Lindau (VHL) tumor suppressor protein.[2] The VHL protein is a component of a larger E3 ubiquitin ligase complex. Upon binding to the hydroxylated HIF-

α, this complex attaches a chain of ubiquitin molecules to the HIF-α subunit. This polyubiquitination serves as a molecular tag, marking the HIF-α protein for rapid recognition and degradation by the 26S proteasome.[1] This entire process is highly efficient, resulting in a very short half-life for HIF-

α (approximately five minutes) under normoxic conditions, thereby preventing its accumulation and downstream activity.[5]

2.2 The Hypoxic Response

The regulatory system pivots dramatically under hypoxic conditions. When cellular oxygen levels fall, the PHD enzymes, which require oxygen as a co-substrate, lose their catalytic activity.[1] Consequently, the hydroxylation of HIF-

α ceases. Without this critical modification, the VHL E3 ubiquitin ligase complex can no longer recognize or bind to the HIF-α subunit. This effectively shuts down the degradation pathway, allowing newly synthesized HIF-α protein to escape destruction and rapidly accumulate within the cell.[2]

The stabilized HIF-α subunit then translocates from the cytoplasm into the nucleus. Inside the nucleus, it forms a stable heterodimer with its partner, the constitutively expressed HIF-β (ARNT) subunit.[2] This HIF-

α/HIF-β heterodimer is the transcriptionally active form of the HIF complex. Along with transcriptional co-activators such as p300/CBP, the active complex binds to specific DNA sequences known as Hypoxia Response Elements (HREs), which are located in the promoter or enhancer regions of hundreds of target genes.[2] The binding of the HIF complex to these HREs initiates a massive and coordinated transcriptional cascade, fundamentally reprogramming cellular physiology to adapt to the low-oxygen environment.[4]

2.3 Downstream Genetic Programs and Pathophysiological Relevance

The genes regulated by the HIF pathway orchestrate a wide array of adaptive responses that are crucial in both normal physiological processes and the progression of various diseases.

2.3.1 Physiological Roles

In normal physiology, HIF activation is essential for development, tissue repair, and adaptation to high altitude. Key downstream programs include:

• Erythropoiesis: HIF directly activates the transcription of the erythropoietin (EPO) gene, primarily in the kidney's interstitial fibroblasts. The resulting EPO protein is a hormone that stimulates the production of red blood cells in the bone marrow, thereby increasing the oxygen-carrying capacity of the blood.[1] This is the central mechanism for correcting anemia.
• Angiogenesis: HIF is a master regulator of new blood vessel formation. It drives the expression of potent pro-angiogenic factors, most notably Vascular Endothelial Growth Factor (VEGF), which promotes the growth of new capillaries to improve oxygen delivery to tissues.[7]
• Metabolic Reprogramming: HIF shifts cellular metabolism away from oxygen-dependent oxidative phosphorylation towards anaerobic glycolysis. It achieves this by upregulating genes encoding glucose transporters (e.g., GLUT1) and glycolytic enzymes, allowing cells to continue producing ATP even in the absence of sufficient oxygen.[1]

2.3.2 Pathophysiological Roles

The same adaptive mechanisms that are beneficial in normal physiology can be co-opted by disease processes, particularly in cancer and chronic kidney disease.

• Cancer: The microenvironment of solid tumors is often characterized by chronic and acute hypoxia due to rapid, disorganized growth that outpaces the blood supply.[2] In this context, HIF activation becomes a major driver of tumor progression and malignancy. It promotes tumor angiogenesis, providing nutrients for growth; facilitates the metabolic switch to glycolysis (the Warburg effect); and activates genes involved in cell survival, invasion, metastasis, and resistance to both chemotherapy and radiation.[2] Consequently, elevated levels of HIF-1$\alpha$ in tumor biopsies are strongly correlated with increased tumor aggressiveness and poorer patient prognosis.[2]
• Anemia in Chronic Kidney Disease (CKD): In patients with CKD, the progressive loss of kidney function leads to the destruction of the EPO-producing cells. This results in deficient endogenous EPO production, which is the primary cause of renal anemia.[1] The HIF pathway's natural role as the upstream regulator of EPO transcription makes it an ideal therapeutic target to reactivate the body's own machinery for red blood cell production.

This dual nature of the HIF pathway—beneficial in correcting anemia but detrimental in promoting cancer—is the central paradox that governs the development of all HIF-modulating drugs. Therapeutic strategies must be carefully tailored to either upregulate or downregulate the pathway depending on the specific disease context. Upregulating HIF activity, as is the goal with HIF-PH inhibitors like HIF-117, is a rational approach for treating anemia. However, this strategy carries an inherent theoretical risk of promoting the growth of occult or pre-existing malignancies, a concern that has been a major focus of regulatory scrutiny for this class of drugs.[15]

2.4 Differentiating HIF-1$\alpha$ and HIF-2$\alpha$

A nuanced understanding of the HIF pathway requires differentiating between its major isoforms, HIF-1$\alpha$ and HIF-2$\alpha$. While they share structural similarities and are regulated by the same PHD-VHL mechanism, they control distinct sets of target genes and play different roles in physiology and disease.[1]

• HIF-1$\alpha$ is expressed ubiquitously in almost all cell types and is considered the master regulator of the metabolic switch to glycolysis under hypoxic conditions.[1]
• HIF-2$\alpha$ exhibits a more restricted tissue expression pattern, being prominent in endothelial cells, hepatocytes, and the EPO-producing interstitial fibroblasts of the kidney. It is the primary regulator of EPO gene expression and also controls a distinct set of genes involved in angiogenesis and iron metabolism.[1]

This isoform specificity has profound implications for therapeutic development. In the context of cancer, particularly in VHL-deficient clear cell renal cell carcinoma (ccRCC), HIF-2$\alpha$ is the key oncogenic driver, while HIF-1$\alpha$ can paradoxically have tumor-suppressive effects.[2] This has led to the development of highly specific HIF-2$\alpha$

inhibitors (e.g., Belzutifan) as a targeted therapy for ccRCC.[18]

Conversely, for the treatment of anemia, the therapeutic goal is to stabilize HIF-α to increase EPO production. Since HIF-2$\alpha$ is the primary driver of EPO, any effective drug for anemia must ensure the robust stabilization of this isoform. HIF Prolyl Hydroxylase inhibitors like HIF-117 are pan-HIF-α stabilizers; by inhibiting the PHD enzymes, they prevent the degradation of all HIF-α isoforms that are regulated by this mechanism. This lack of isoform specificity is acceptable for the treatment of anemia, as the stabilization of both HIF-1$\alpha$ and HIF-2$\alpha$ contributes to the desired physiological response, including improved iron metabolism. This fundamental biological distinction explains the divergent development paths within the field of HIF modulation: isoform-specific inhibitors for oncology and pan-stabilizers for anemia.

Section 3: HIF-117 (SSS17): Profile of an Investigational Antianemic Agent

HIF-117 is an investigational drug positioned at the forefront of a new therapeutic class aimed at treating anemia. Its development represents a strategic initiative by a major player in the Chinese biopharmaceutical market to innovate within a core area of expertise.

3.1 Drug Identity and Formulation

HIF-117 is a small-molecule compound designed for oral administration.[20] It is being developed in a capsule formulation.[21] The drug is classified as an antianemic agent and is also referred to by the internal development code SSS17.[21] Throughout this report, the designation "HIF-117 (SSS17)" will be used to ensure clarity and acknowledge both identifiers present in the available documentation. As a new molecular entity, it represents a novel chemical structure intended to provide a new therapeutic option for patients.[22]

3.2 Developer: 3SBio Inc. and Shenyang Sunshine Pharmaceutical

The originator and developer of HIF-117 (SSS17) is 3SBio Inc., a prominent, fully integrated biotechnology company based in China.[22] 3SBio has established a significant presence in the Chinese pharmaceutical market with a focus on key therapeutic areas, including nephrology, oncology, and autoimmune diseases.[23] The direct development and clinical trial sponsorship of HIF-117 are being conducted by Shenyang Sunshine Pharmaceutical Co., Ltd., a subsidiary of 3SBio.[21]

3SBio's foray into the HIF-PHI space is a well-calculated strategic move. The company is already a market leader in the treatment of CKD anemia in China with its flagship product, EPIAO, a recombinant human erythropoietin (rhEPO).[23] The development of HIF-117 represents a classic example of an incumbent pharmaceutical firm investing in a potentially disruptive technology that could, over time, cannibalize the market for its own legacy product. This strategy is both defensive and offensive. Defensively, it allows 3SBio to maintain its leadership in the nephrology market as the standard of care evolves from injectable biologics to oral small molecules. Offensively, it positions the company to capture market share from other ESA producers by offering a next-generation therapy with potential advantages in convenience and safety. The company's own statements reflect this strategy, noting that SSS17 is expected to "create synergies" with its existing rhEPO injections and provide CKD patients with "more options of full-cycle and comprehensive treatments," suggesting a plan for market segmentation and product life-cycle management.[21]

3.3 Clarification of Naming Conventions and Exclusion of Irrelevant Data

A comprehensive analysis of HIF-117 requires the explicit clarification of potential points of confusion arising from homonymous or similarly coded entities found during research. Failure to disambiguate these terms could lead to significant misinterpretation of the drug's corporate and regulatory context.

• HIF Global: It is critical to distinguish the pharmaceutical agent HIF-117 from "HIF Global." HIF Global is a Houston, Texas-based company operating in the energy sector. It is a world leader in the development and production of "e-Fuels"—synthetic fuels created using green hydrogen (produced via electrolysis with renewable energy) and recycled carbon dioxide.[28] The company has prominent partners, including Porsche and Mitsui O.S.K. Lines, and operates the world's first integrated e-Fuels facility in Chile.[29] There is no operational, financial, or scientific connection between HIF Global and the biopharmaceutical company 3SBio or its drug candidate, HIF-117. The shared acronym "HIF" is purely coincidental.
• Irrelevant Regulatory Sections: Database searches for "HIF-117" may incorrectly retrieve references to specific sections of US law and regulations that bear the number 117. These include:
• 21 Code of Federal Regulations (CFR) Part 117: This is a regulation enforced by the U.S. Food and Drug Administration (FDA) that pertains to "Current Good Manufacturing Practice, Hazard Analysis, and Risk-Based Preventive Controls for Human Food".[33] It is part of the Food Safety Modernization Act (FSMA) and is entirely unrelated to the regulation of pharmaceutical products.
• Section 117 of the U.S. Patents Act: This section of patent law deals with the concept of indirect or contributory infringement, defining circumstances under which the supply of a product can constitute an infringement of a patent, even if the supplier does not directly perform the patented method.[35] While relevant to patent law in general, it has no specific connection to the drug HIF-117 itself.
• Section 117 of the Higher Education Act: This section requires U.S. institutions of higher education to disclose gifts from and contracts with foreign sources.[36] It is unrelated to pharmaceutical development.

These entities and regulations are explicitly excluded from this analysis as they are not pertinent to the identity, development, or intellectual property of the drug HIF-117.

Section 4: Pharmacodynamics and Mechanism of Action

The pharmacological activity of HIF-117 (SSS17) is designed to harness the body's innate oxygen-sensing pathway to generate a therapeutic response for anemia. As a member of the HIF-PHI class, its mechanism of action is distinct from and upstream of traditional ESA therapies, offering a more integrated approach to stimulating erythropoiesis.

4.1 Inhibition of Prolyl Hydroxylase

The primary molecular target of HIF-117 is the family of HIF prolyl hydroxylase (PHD) enzymes.[20] These enzymes, also known as Egl-9 family hypoxia-inducible factors (EGLNs), are the key negative regulators of the HIF pathway.[22] HIF-117 acts as a selective, small-molecule inhibitor of these enzymes.[21]

By binding to the active site of the PHD enzymes, HIF-117 competitively inhibits their function. This blockade prevents the critical hydroxylation of proline residues on the HIF-α subunits.[1] As described in Section 2, this hydroxylation step is the prerequisite for recognition and binding by the VHL E3 ubiquitin ligase complex. Therefore, by inhibiting PHD activity, HIF-117 effectively disrupts the signal for HIF-

α degradation, leading to its stabilization and accumulation within the cell.[1]

4.2 Pharmacological Induction of the Hypoxic Response

The inhibition of PHD enzymes by HIF-117 allows HIF-α to accumulate even under normal oxygen conditions. This pharmacologically induced stabilization creates a state often referred to as "pseudohypoxia," where the cell's transcriptional machinery behaves as if it were in a low-oxygen environment.[1] This leads to the activation of the full downstream HIF-mediated transcriptional program, which includes a coordinated set of responses ideally suited to correct anemia.

The two most important consequences of this induced hypoxic response are:

1. Increased Endogenous Erythropoietin (EPO) Production: The stabilized HIF-α (primarily HIF-2$\alpha$) translocates to the nucleus, dimerizes with HIF-β, and binds to the HRE in the promoter of the EPO gene. This stimulates the transcription and subsequent secretion of endogenous EPO from the kidneys and, to a lesser extent, the liver.[1] The resulting increase in circulating EPO levels acts on erythroid progenitor cells in the bone marrow to promote their proliferation and differentiation into mature red blood cells, thereby increasing hemoglobin concentration and red blood cell mass.[14]
2. Improved Iron Metabolism: A crucial and differentiating aspect of the HIF-PHI mechanism is its effect on iron homeostasis. HIF activation leads to the transcriptional suppression of hepcidin, a peptide hormone produced by the liver that is the master negative regulator of iron availability.[1] High levels of hepcidin, often seen in inflammatory states like CKD, block iron absorption from the intestine and trap iron within macrophages and hepatocytes, leading to functional iron deficiency. By decreasing hepcidin levels, HIF-117 is expected to increase the absorption of dietary iron and promote the mobilization of stored iron. This leads to an increase in serum transferrin and total iron-binding capacity (TIBC), ensuring that a sufficient supply of iron is available to the bone marrow for incorporation into the hemoglobin of newly forming red blood cells.[1]

4.3 A Physiological vs. Pharmacological Approach to Anemia Correction

The mechanism of action of HIF-PHIs like HIF-117 stands in stark contrast to that of conventional ESAs. This mechanistic difference is the central tenet of the value proposition for this new class of drugs.

• ESAs (e.g., Epoetin Alfa): These are injectable, recombinant versions of the EPO hormone. They act directly on the EPO receptor on bone marrow progenitor cells to stimulate erythropoiesis. This approach bypasses the body's natural regulatory feedback loops and often results in large, supraphysiological spikes in serum EPO concentrations that are not coordinated with iron availability.[6] The lack of effect on iron metabolism means that ESA therapy frequently requires the co-administration of intravenous iron to meet the increased demand of the stimulated bone marrow.[1]
• HIF-PH Inhibitors (e.g., HIF-117): These drugs act upstream, engaging the body's own integrated system for managing erythropoiesis. Instead of supplying an external hormone, they trigger the natural, coordinated production of endogenous EPO while simultaneously improving the availability of iron, the key building block for hemoglobin.[1] This integrated mechanism is hypothesized to produce more physiological and balanced levels of EPO and to be more effective in patients with inflammation-driven functional iron deficiency. This holistic approach represents a potential fundamental advantage over ESAs, offering the possibility of more efficient anemia correction with a potentially reduced need for supplemental intravenous iron, which carries its own risks and costs.

Section 5: Clinical Development Program of HIF-117 (SSS17)

The clinical development of HIF-117 (SSS17) is in its early stages, focusing on establishing the foundational safety, tolerability, and pharmacokinetic (PK) profile of the drug. The program is being executed with a clear and deliberate focus on the Chinese domestic market, with all known trials being conducted within China and enrolling Chinese subjects.

5.1 Regulatory Initiation

The formal clinical development journey for HIF-117 began on November 12, 2019, when the clinical trial application for the HIF-117 Capsule was officially approved by China's National Medical Products Administration (NMPA). This approval granted 3SBio and Shenyang Sunshine Pharmaceutical the authority to proceed with human clinical trials in China.[21]

5.2 Phase 1 Clinical Trials

Several Phase 1 studies have been initiated to characterize the behavior of HIF-117 in healthy human volunteers. The information available suggests a standard early-phase program designed to assess single and multiple ascending doses.

• SYSS-SSS17-UND-I-01: This was the first-in-human study for SSS17. It was designed as a single-center, randomized, single-blind, placebo-controlled, single dose-escalation trial. The primary objectives were to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics (PD) of single oral doses of SSS17. The study planned to enroll approximately 65 healthy subjects aged 18 to 60 years, with 53 receiving the active drug and 12 receiving a placebo. While one source lists the trial status as "Unknown," it also indicates the trial "Ended 4 years ago," suggesting it has been completed.[26]
• SYSS-SSS17-UND-I-02: This Phase 1 trial was designed to expand on the initial findings by evaluating both single and multiple doses. The study aimed to investigate the efficacy, safety, PK, and PD of single oral doses of 5 mg, 15 mg, 20 mg, and 25 mg of SSS17, as well as multiple oral administrations of 15 mg and 20 mg, compared with placebo. The target population was healthy subjects aged 18 to 45 years. The trial status is listed inconsistently as both "Recruiting" and "Ended 2 years ago," which likely indicates the trial is complete and the database status has not been uniformly updated.[40]
• NCT07024888: This identifier is associated with a Phase 1 pharmacokinetics trial conducted in healthy volunteers in China. The trial was sponsored by Shenyang Sunshine Pharmaceutical and, according to one database, was completed on May 28, 2025.[22] It is highly probable that this NCT number corresponds to one of the previously mentioned studies, providing a formal registration identity for the trial in international databases.

5.3 Planned and Future Studies

The development plan for HIF-117 (SSS17) includes further characterization in healthy subjects and the transition into patient populations.

• Mass Balance Study: A Phase 1 study is planned to evaluate the absorption, distribution, metabolism, and excretion (ADME) of the drug. This trial will use a radiolabeled version of the compound, [¹⁴C]SSS17, administered to healthy Chinese male subjects to trace the drug's fate in the body. The trial is listed with a "Not yet recruiting" status.[27]
• Food-Effect Study (NCT06854276): A Phase 2 study is planned to evaluate the effect of food on the pharmacokinetics of SSS17 capsules in healthy Chinese subjects. Understanding how food intake affects the drug's absorption is a standard and crucial step in defining the optimal dosing instructions. This study is also listed as "Not yet recruiting".[41]
• Phase 2 Patient Study: The next major step in the program is a Phase 2 dose-finding clinical study. This trial will be the first to evaluate the efficacy and safety of oral SSS17 capsules in the target patient population: individuals with anemia associated with non-dialysis chronic kidney disease (NDD-CKD).[20] The results of this study will be critical for selecting the optimal dose for subsequent pivotal Phase 3 trials.

The progression of the clinical program from healthy volunteer studies to patient trials follows a logical and standard drug development pathway. The focus on Chinese subjects in all identified trials underscores the company's "China-first" strategy. This approach enables 3SBio to generate data directly applicable to its primary market and its primary regulator, the NMPA, potentially streamlining the path to approval in China. However, it also means that the drug's global potential remains an open question, as data from a solely Chinese population may require supplementary bridging studies to support registration with Western regulatory agencies like the FDA and the European Medicines Agency (EMA).

Table 1: Summary of HIF-117 (SSS17) Clinical Trials

Trial Identifier	Phase	Status	Population	Brief Description / Objectives	Source(s)
SYSS-SSS17-UND-I-01	Phase 1	Completed	Healthy Volunteers	First-in-human, single ascending dose (SAD) study to evaluate safety, tolerability, PK, and PD.	26
SYSS-SSS17-UND-I-02	Phase 1	Completed	Healthy Volunteers	Single and multiple ascending dose (MAD) study to evaluate safety, efficacy, tolerability, PK, and PD.	40
NCT07024888	Phase 1	Completed	Healthy Volunteers	Pharmacokinetics trial. Likely the formal identifier for one of the above studies.	22
Not Specified	Phase 1	Not Yet Recruiting	Healthy Volunteers	Mass balance study using radiolabeled [¹⁴C]SSS17 to assess ADME.	27
NCT06854276	Phase 2	Not Yet Recruiting	Healthy Volunteers	Study to evaluate the effect of food on the pharmacokinetics of SSS17.	41
Not Specified	Phase 2	Planned	NDD-CKD Patients	Dose-finding study to evaluate efficacy and safety in the target patient population.	20

Section 6: Therapeutic Landscape: Anemia in Chronic Kidney Disease (CKD)

The development of HIF-117 (SSS17) is aimed at addressing a significant and persistent unmet need in the management of Chronic Kidney Disease (CKD), a global health issue affecting millions of people. Anemia is one of the most common and debilitating complications of CKD, profoundly impacting patient quality of life and clinical outcomes.

6.1 Pathophysiology and Unmet Need

Anemia in CKD is a multifactorial condition. The primary driver is the insufficient production of the hormone erythropoietin (EPO) due to the progressive damage to the EPO-producing interstitial cells in the kidneys.[13] As kidney function declines, EPO levels fall, leading to inadequate stimulation of red blood cell production in the bone marrow.

A second critical factor is disordered iron homeostasis. CKD is often considered a state of chronic inflammation, which leads to elevated levels of the hormone hepcidin. Hepcidin blocks the absorption of iron from the gut and sequesters iron in storage sites, preventing its mobilization for use in hemoglobin synthesis. This results in a condition known as functional iron deficiency, where the body has adequate iron stores but cannot access them effectively.[1]

The clinical consequences of CKD anemia are severe. Patients often experience debilitating fatigue, reduced exercise capacity, cognitive impairment, and a significantly diminished quality of life. Furthermore, anemia is an independent risk factor for adverse clinical outcomes, including an increased risk of cardiovascular events, hospitalization, and mortality.[6]

6.2 Current Standard of Care: ESAs and Iron

For over three decades, the cornerstone of treatment for CKD anemia has been therapy with Erythropoiesis-Stimulating Agents (ESAs). These are injectable, recombinant forms of human EPO (e.g., epoetin alfa, darbepoetin alfa) that directly stimulate the bone marrow to produce red blood cells.[6] To be effective, ESA therapy must be accompanied by adequate iron supplies, which often necessitates the administration of intravenous (IV) iron, particularly in dialysis patients.[6]

While ESAs are effective at increasing hemoglobin levels and reducing the need for blood transfusions, their use is tempered by significant safety concerns. Large-scale clinical trials have demonstrated that targeting higher, near-normal hemoglobin levels with ESAs is associated with an increased risk of serious and life-threatening adverse events, including hypertension, stroke, myocardial infarction, venous thromboembolism, and increased mortality.[6] These findings have led to regulatory agencies, including the FDA, issuing "black box" warnings on ESA labels, advising clinicians to use the lowest possible dose to avoid red blood cell transfusions. This creates a difficult therapeutic balancing act, where the goal is to alleviate the symptoms of anemia without exposing patients to undue cardiovascular risk.

6.3 The Emergence of HIF-PH Inhibitors

The development of HIF Prolyl Hydroxylase inhibitors, including HIF-117, represents the most significant paradigm shift in the treatment of CKD anemia since the introduction of ESAs. This class of drugs offers two fundamental potential advantages over the current standard of care.

First is the convenience of oral administration. For patients with CKD, particularly those not yet on dialysis (NDD-CKD), the ability to take a daily or thrice-weekly pill instead of receiving regular injections offers a substantial improvement in convenience and quality of life, and may improve treatment adherence.[6]

Second, and more importantly, is the potential for an improved safety profile. As discussed in Section 4, the mechanism of HIF-PHIs is thought to induce a more physiological and coordinated erythropoietic response compared to the supraphysiological stimulation of ESAs.[1] The market opportunity for HIF-PHIs is therefore driven not just by the prospect of equivalent efficacy in an oral formulation, but by the crucial hope that this more physiological mechanism will translate into a reduced risk of the cardiovascular and thromboembolic events that have plagued ESA therapy. The commercial success of any new HIF-PHI, including HIF-117, will ultimately depend on its ability to deliver on this promise of improved safety in large, long-term clinical outcome trials.

Section 7: Competitive and Comparative Analysis

HIF-117 (SSS17) is entering a well-defined but highly competitive therapeutic class. The development and regulatory history of its predecessors have established clear benchmarks for efficacy and, most critically, for cardiovascular safety. A thorough analysis of these competitors is essential to understand the challenges and opportunities that lie ahead for HIF-117.

7.1 Profile of Approved and Late-Stage HIF-PHIs

Several HIF-PHIs have advanced through late-stage clinical trials and have achieved regulatory approval in various global markets. Their experiences provide a crucial roadmap for the development of HIF-117.

• Roxadustat (FG-4592): Developed by FibroGen and partnered with AstraZeneca and Astellas, Roxadustat was the first-in-class HIF-PHI to reach the market. It is approved for the treatment of anemia in CKD patients (both non-dialysis and dialysis-dependent) in China, Japan, and Europe.[38] Despite its approvals elsewhere, Roxadustat has not been approved in the United States. The FDA issued a Complete Response Letter, citing concerns about its cardiovascular safety profile and requesting additional clinical data.[15] Clinical trials have shown Roxadustat to be effective at increasing hemoglobin and improving iron metabolism, but the cardiovascular risk profile remains a point of contention for US regulators.[48]
• Daprodustat (GSK1278863, brand name Jesduvroq): Developed by GSK, Daprodustat has achieved a key regulatory milestone. In February 2023, it became the first and only HIF-PHI to be approved by the U.S. FDA.[53] However, its approval is restricted to the treatment of anemia in CKD patients who have been on dialysis for at least four months.[43] It is not approved for non-dialysis patients in the US. The approval was based on the large ASCEND clinical trial program, which demonstrated that Daprodustat was non-inferior to ESAs with respect to Major Adverse Cardiovascular Events (MACE) in the dialysis-dependent population.[45] It is also approved in Japan and the EU.[53]
• Vadadustat (AKB-6548): Developed by Akebia Therapeutics, Vadadustat's regulatory path in the US has been challenging. The drug demonstrated non-inferiority to an ESA on cardiovascular safety in the dialysis-dependent patient population but failed to meet the non-inferiority margin for MACE in the non-dialysis-dependent population.[55] Consequently, the FDA issued a Complete Response Letter, declining to approve the drug for either patient population, citing an unfavorable risk-benefit assessment, particularly for non-dialysis patients where the risks were not justified by the benefits of an oral alternative.[15]
• Other Competitors: The field includes other HIF-PHIs such as Enarodustat (JTZ-951) and Molidustat (BAY 85-3934), which are approved in Japan, further populating the competitive landscape, particularly in Asian markets.[20]

7.2 Efficacy and Safety Benchmarks

The collective data from these competitor programs establish clear expectations for HIF-117.

• Efficacy: The efficacy bar is well-defined and high. A new HIF-PHI must demonstrate, at a minimum, non-inferiority to the current standard of care (ESAs) in its ability to increase and maintain hemoglobin levels within the target range (typically 10-11 g/dL).[39] All major HIF-PHIs have successfully met this endpoint in their pivotal trials.[48]
• Safety: Cardiovascular safety is the paramount hurdle and the key point of differentiation. The regulatory history of the class unequivocally demonstrates that achieving statistical non-inferiority for MACE versus ESAs is the critical gatekeeper to market approval, especially in the US and Europe. The divergent outcomes for Daprodustat (approved in DD-CKD), Vadadustat, and Roxadustat (both not approved in the US) highlight two crucial points. First, the safety profile can differ between the dialysis-dependent (DD-CKD) and non-dialysis-dependent (NDD-CKD) populations. Regulators have shown themselves willing to approve a drug for one population but not the other based on the risk-benefit analysis. Second, the non-dialysis population appears to be a higher-risk group for cardiovascular events with HIF-PHI therapy, and represents both the greatest clinical challenge and the largest potential commercial opportunity if a drug can prove its safety in this setting. For HIF-117 to be successful globally, its future Phase 3 program must be designed with sufficient statistical power to rigorously assess cardiovascular outcomes and demonstrate a clean safety profile.

Table 2: Comparative Profile of Leading HIF-PH Inhibitors

Drug Name	Developer(s)	Efficacy vs. ESA	Cardiovascular Safety (MACE Outcome vs. ESA)	US Regulatory Status	EU Regulatory Status	China/Japan Status
HIF-117 (SSS17)	3SBio / Shenyang Sunshine	Data Not Available	Data Not Available	Not Filed	Not Filed	In Phase 1/2
Roxadustat	FibroGen / AstraZeneca / Astellas	Non-inferior	Did not meet FDA's safety criteria	Not Approved	Approved	Approved
Daprodustat	GSK	Non-inferior	Non-inferior in DD-CKD; Met non-inferiority in NDD-CKD	Approved (DD-CKD only)	Approved	Approved (Japan)
Vadadustat	Akebia Therapeutics	Non-inferior	Non-inferior in DD-CKD; Failed to meet non-inferiority in NDD-CKD	Not Approved	Approved	Approved (Japan)

DD-CKD: Dialysis-Dependent Chronic Kidney Disease; NDD-CKD: Non-Dialysis-Dependent Chronic Kidney Disease.

Section 8: Broader Therapeutic Potential and Future Directions

While the primary development focus for HIF-117 and its class is unequivocally the treatment of anemia in CKD, the fundamental role of the HIF pathway in cellular adaptation to hypoxia suggests a broader, albeit more speculative, range of therapeutic applications. The mechanism of action—promoting angiogenesis, reprogramming metabolism, and enhancing cell survival—could theoretically be beneficial in a variety of other disease states characterized by ischemia or tissue damage.

8.1 Beyond CKD-Anemia

Preclinical and early clinical research have explored the potential of HIF stabilization in several other indications. These represent high-risk, high-reward opportunities for indication expansion, contingent on a thorough understanding of the specific pathophysiology and a favorable risk-benefit profile.

• Ischemic Diseases: Conditions such as myocardial infarction, peripheral artery disease, and ischemic stroke are characterized by a lack of blood flow and oxygen to critical tissues. In animal models, the administration of HIF-PH inhibitors before or immediately after an ischemic event has been shown to reduce infarct size and improve functional outcomes.[37] The proposed mechanisms include the upregulation of pro-angiogenic factors to restore blood flow, metabolic reprogramming to help cells survive the ischemic insult, and activation of tissue repair and stem cell homing pathways.[8] However, translating these preclinical findings to the clinic is challenging, as the timing of intervention is critical and the complex inflammatory environment of ischemic tissue could lead to unpredictable effects.
• Inflammation and Wound Healing: The HIF pathway is intricately linked with the immune system and tissue repair processes. HIF-1$\alpha$ modulation has been shown to have a regenerative effect on skin cells, and in preclinical models, was able to accelerate the healing of chronic wounds in diabetic and aged mice.[7] The potential to treat inflammatory conditions is also being explored, given HIF's role in regulating the function of immune cells like macrophages and T-cells.[37] This area is complex, as HIF can exert both pro- and anti-inflammatory effects depending on the cellular context and timing.
• Anti-Aging and Related Morbidities: Emerging preclinical research has linked HIF pathway activation to the mitigation of age-related decline. A patent application describes the use of a HIF-PH inhibitor, BGE-117, to treat conditions such as sarcopenia (age-related muscle loss), frailty, and the unexplained anemia of aging.[57] In aged mice, treatment with BGE-117 was shown to increase voluntary activity and raise hemoglobin levels, even in the presence of inflammation.[57] This suggests a potential role for HIF-PHIs in addressing the broader systemic decline associated with aging.

While these potential applications are biologically plausible, they carry significant risks. The very mechanisms that could be beneficial—such as promoting cell proliferation and angiogenesis—are the same mechanisms that drive cancer. Therefore, any exploration of HIF-PHIs in non-anemia indications will require an extremely cautious approach and rigorous long-term safety monitoring to rule out any increased risk of malignancy or other unintended consequences, such as the worsening of diabetic retinopathy through unwanted angiogenesis. For a developer like 3SBio, the most prudent strategy is to focus on securing approval for HIF-117 in the well-defined indication of CKD anemia before dedicating significant resources to these higher-risk expansion opportunities.

8.2 HIF Inhibition in Oncology

To provide a complete picture of the therapeutic landscape for HIF modulation, it is important to contrast the strategy of HIF stabilization (for anemia) with the opposite approach of HIF inhibition (for cancer). As established, HIF activation is a key survival mechanism for tumor cells in a hypoxic microenvironment.[2] Therefore, a major focus of oncology research is the development of drugs that can block HIF activity.

These anti-cancer agents work through various mechanisms, including inhibiting HIF-α synthesis, preventing its dimerization with HIF-β, or blocking its ability to bind to DNA.[2] The most clinically advanced strategy involves the direct, isoform-specific inhibition of HIF-2$\alpha$. The drug Belzutifan, a selective HIF-2$\alpha$ inhibitor, has been approved by the FDA for the treatment of VHL disease-associated renal cell carcinoma and other tumors, validating this therapeutic approach.[17] This parallel field of HIF inhibition underscores the context-dependent, "two-faced" nature of the HIF pathway, where its activity must be either promoted or suppressed depending on the specific disease being treated.

Section 9: Intellectual Property and Regulatory Outlook

The commercial viability of HIF-117 (SSS17) will depend not only on its clinical performance but also on the strength of its intellectual property (IP) protection and its ability to navigate a well-defined but stringent regulatory pathway.

9.1 Patent Landscape for HIF Modulators

The therapeutic field of HIF modulation is a mature and competitive area of research, which is reflected in a dense and active patent landscape. A recent review of patent activity from 2021-2023 identified numerous new patents covering a wide range of HIF modulators, including both HIF upregulators (like PHD inhibitors) and HIF downregulators (like direct HIF-α inhibitors and degraders).[58] This indicates that innovation is ongoing and that companies are actively seeking to protect new chemical matter and therapeutic applications.

Patents in this space cover several aspects of the invention:

• Composition of Matter: These patents protect the novel chemical structures of the HIF-modulating compounds themselves. For a new molecular entity like HIF-117, a strong composition of matter patent is the most valuable form of IP protection. While the specific patent for HIF-117 is not identified in the provided materials, a patent granted to Shenyang Sunshine Pharmaceutical (US Patent 10,149,841) covers a class of "Compound of 3-hydroxyl pyridine" derivatives for use in inhibiting HIF prolyl hydroxylase, which may be relevant to the chemical scaffold of HIF-117.[60]
• Method of Use: These patents cover the use of HIF modulators for treating specific diseases. Examples from the research include patents for the use of HIF-PHIs to treat manganese toxicity or aging-related conditions.[57]
• Formulations and Crystalline Forms: Companies also seek patent protection for specific formulations, salts, or crystalline forms of a drug, which can provide advantages in stability, bioavailability, or manufacturing, and can extend the period of market exclusivity.[63]

Given the competitive environment, it is almost certain that 3SBio has secured, or is in the process of securing, robust patent protection for HIF-117 in its key markets, beginning with China.

9.2 Regulatory Outlook

The regulatory pathway for HIF-PH inhibitors for the treatment of CKD anemia is now well-established, but it is also fraught with challenges. The experiences of Roxadustat, Daprodustat, and Vadadustat with global regulatory agencies, particularly the U.S. FDA, provide a clear set of expectations and precedents for HIF-117.

The primary regulatory hurdle is the demonstration of long-term cardiovascular safety. Regulators require that any new drug for CKD anemia demonstrate that it does not unacceptably increase the risk of Major Adverse Cardiovascular Events (MACE) when compared to the existing standard of care, ESAs.[15] This requires large, expensive, and lengthy Phase 3 cardiovascular outcome trials.

The FDA's decisions have established a high bar for approval:

• Non-Inferiority is Essential: The MACE data must meet a pre-specified statistical threshold for non-inferiority. Failure to meet this threshold, as was the case for Vadadustat in the non-dialysis population, is a primary reason for non-approval.[56]
• Population-Specific Risk-Benefit: The FDA has shown that it will evaluate the risk-benefit profile separately for dialysis-dependent and non-dialysis-dependent patients. The approval of Daprodustat for only the dialysis population demonstrates that a drug can be deemed to have a favorable profile in one group but not the other.[53]
• Overall Safety Profile: Beyond MACE, regulators will scrutinize the entire safety database for any other signals of concern, such as thromboembolic events, which have been a topic of discussion for the class.[16]

Given 3SBio's current "China-first" development strategy, the initial regulatory submission for HIF-117 will be to the NMPA. The NMPA's standards and priorities may differ from those of the FDA or EMA, and it is possible that the path to market in China could be faster. However, for HIF-117 to achieve global commercial success, it will ultimately need to generate a robust Phase 3 data package that can satisfy the stringent cardiovascular safety requirements of Western regulators.

Section 10: Strategic Analysis and Concluding Assessment

HIF-117 (SSS17) represents a significant pipeline asset for 3SBio, one that is strategically aligned with the company's existing strengths and the evolving therapeutic landscape. However, its path to market is characterized by substantial opportunities and formidable threats that will require expert clinical and strategic execution.

10.1 SWOT Analysis

A systematic analysis of the drug's Strengths, Weaknesses, Opportunities, and Threats provides a clear framework for assessing its overall position.

• Strengths:
• Oral Administration: The convenience of an oral pill is a major advantage over injectable ESAs, particularly for non-dialysis patients, potentially improving patient compliance and quality of life.
• Novel Mechanism of Action: The HIF-PHI mechanism offers a more physiological approach to anemia correction by coordinating endogenous EPO production with iron mobilization, which may reduce the need for IV iron.
• Strong Developer: 3SBio is an established leader in the Chinese nephrology market with deep commercial and regulatory experience, providing a strong platform for a successful domestic launch.
• Weaknesses:
• Early Stage of Development: HIF-117 is still in early-phase clinical trials. There is no publicly available efficacy or long-term safety data in the target patient population, making its ultimate profile highly uncertain.
• Lack of Isoform Specificity: As a pan-HIF-α stabilizer, it shares the class-wide theoretical risk of off-target effects related to the stabilization of HIF-1$\alpha$, which could be relevant to long-term safety.
• China-Centric Data: The current clinical program is limited to Chinese subjects, which may require additional bridging studies to support registration in Western markets.
• Opportunities:
• Significant Unmet Need: There remains a substantial need for safer and more convenient alternatives to ESAs for the millions of CKD patients suffering from anemia.
• Dominance in the Chinese Market: Leveraging 3SBio's existing infrastructure, HIF-117 has the potential to become the leading oral anemia therapy in the large and growing Chinese market.
• Success in NDD-CKD Population: If HIF-117 can successfully demonstrate cardiovascular safety in the non-dialysis population—a hurdle where several competitors have stumbled—it could capture a very significant global market segment.
• Potential for Indication Expansion: A proven long-term safety profile could open the door to exploring high-value secondary indications in ischemic diseases or inflammation.
• Threats:
• Intense Competition: The HIF-PHI market is already crowded with approved drugs (Roxadustat, Daprodustat, etc.) and other pipeline candidates, creating a high barrier to entry and likely leading to significant pricing pressure.
• Cardiovascular Safety Risk: This is the single greatest threat to the program. The entire class is under scrutiny for potential cardiovascular and thromboembolic risks. An unfavorable outcome in a Phase 3 MACE trial would be catastrophic for the drug's prospects.
• High Bar for Differentiation: To succeed, HIF-117 must not only be safe and effective but must also demonstrate a clear differentiating advantage over its many competitors, which will be a significant challenge.

10.2 Concluding Assessment

HIF-117 (SSS17) is a strategically coherent and valuable asset for 3SBio. It represents a logical evolution of the company's product portfolio, allowing it to innovate within its core nephrology franchise and prepare for the market shift from injectable ESAs to oral HIF-PHIs. The "China-first" development strategy is a prudent approach that leverages the company's regional strengths and may provide a faster path to an initial market launch.

However, the ultimate success of HIF-117, particularly on a global scale, is far from guaranteed. The program faces two overarching challenges that will define its future. First, it must contend with a crowded and highly competitive market. With several HIF-PHIs already approved, HIF-117 will need to demonstrate a compelling value proposition to gain market share. Second, and most critically, it must overcome the significant cardiovascular safety hurdle that has challenged the entire class. The regulatory precedents set by its competitors are clear: robust, long-term data demonstrating non-inferiority to ESAs on MACE outcomes is a non-negotiable requirement for approval in major Western markets.

For investors, partners, and clinicians, the key question remains unanswered: can HIF-117 deliver a safety and efficacy profile that is not just comparable, but meaningfully differentiated from the existing options? Until data from large-scale, pivotal Phase 3 trials become available, the global potential of HIF-117 will remain a promising but speculative proposition. Its journey through clinical development will be a critical test of both the molecule's properties and 3SBio's ability to execute a complex, high-stakes clinical program in a competitive global arena.

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