HSK-21542 (Anrikefon): A Comprehensive Clinical and Pharmacological Profile of a Novel Peripherally Restricted KOR Agonist

I. Executive Summary

HSK-21542, developed by Sichuan Haisco Pharmaceutical under the trade name Anrikefon, is a novel, intravenously administered, peripherally restricted kappa-opioid receptor (KOR) agonist.[1] It represents a significant advancement in the fields of analgesia and antipruritics, engineered to provide potent therapeutic effects while circumventing the severe central nervous system (CNS) liabilities that have limited the use of traditional mu-opioid receptor (MOR) agonists and earlier generations of KOR agonists.[4] Its core value proposition lies in its ability to selectively target peripheral KORs, thereby blocking pain and itch signals at their source without crossing the blood-brain barrier, thus avoiding side effects such as respiratory depression, addiction, dysphoria, and hallucinations.[4]

The clinical development program for HSK-21542 has yielded robust evidence of its efficacy and safety. In pivotal Phase III trials for the management of postoperative pain following abdominal surgery, HSK-21542 demonstrated statistically significant superiority over placebo. Furthermore, it proved to be non-inferior to the active comparator tramadol in analgesic efficacy but with a markedly improved safety profile, particularly inducing fewer gastrointestinal adverse events.[4] These compelling results led to its regulatory approval in China in May 2025 for the treatment of postoperative pain, where it is uniquely classified as a non-narcotic "white prescription" analgesic, greatly facilitating its clinical adoption.[1]

In parallel, HSK-21542 has shown significant promise in treating chronic kidney disease-associated pruritus (CKD-aP) in patients undergoing hemodialysis. Clinical trials have identified an optimal dose (0.3 µg/kg) that effectively reduces itch intensity and improves patient quality of life with a favorable safety profile.[4] The drug is currently in the preregistration phase in China for this indication.[1]

With a clean pharmacokinetic profile characterized by minimal metabolism and a clear excretion pathway, combined with a well-tolerated safety record across diverse patient populations, HSK-21542 is strongly positioned to address a substantial unmet medical need. Its ongoing development for additional indications, such as pain following orthopedic surgery and postoperative nausea and vomiting, signals a strategic plan for life-cycle expansion. HSK-21542 stands as a leading example of a new generation of peripherally acting therapies poised to redefine the standards of care for pain and itch management.

II. Molecular Profile and Pharmacological Basis

Chemical Identity and Structure

HSK-21542, also known by its trade name Anrikefon, is a new molecular entity classified as both a small molecule and a synthetic short-chain polypeptide.[1] Its precise chemical identity is defined by the IUPAC name: (R)-N-((R)-1-(2-acetyl-2,7-diazaspiro[3.5]nonan-7-yl)-6-amino-1-oxohexan-2-yl)-2-((R)-2-((R)-2-amino-3-phenylpropanamido)-3-phenylpropanamido)-4-methylpentanamide.[14]

The compound's molecular formula is C39​H57​N7​O5​, corresponding to a molecular weight of approximately 703.91 g/mol.[14] Its structure is based on a 7-(D-phenylalanyl-D-phenylalanyl-D-leucyl-D-lysyl)-2-acetyl-2,7-diazaspiro (3.5) nonane backbone.[4] This specific and complex molecular architecture is the result of rational drug design, engineered to confer high selectivity and affinity for its target receptor while restricting its ability to cross the blood-brain barrier.[4] For research and commercial purposes, it is available as Anrikefon and its acetate salt form, Anrikefon acetate.[15]

Mechanism of Action: Selective, Peripherally Restricted Kappa-Opioid Receptor (KOR) Agonism

HSK-21542 functions as a potent and highly selective agonist of the kappa-opioid receptor (KOR), a member of the G-protein coupled receptor (GPCR) family.[4] Its therapeutic action is confined almost exclusively to KORs located in the peripheral nervous system, a critical distinction from traditional opioid analgesics like morphine, which primarily act on mu-opioid receptors (MORs) in the CNS and are associated with severe liabilities including addiction, respiratory depression, and constipation.[4]

Upon binding to peripheral KORs on sensory nerve endings and dorsal root ganglia, HSK-21542 initiates a signaling cascade. Through the involvement of G-proteins, it synergistically modulates transmembrane ion flow, primarily by regulating potassium and calcium channels.[4] This action hyperpolarizes the neuronal membrane, effectively curbing the excitability of sensory nerves. By inhibiting the transmission of nociceptive (pain) and pruritic (itch) signals from the periphery to the spinal cord and brain, it blocks these sensations at their origin.[4] Additionally, it has been shown to decrease the local release of inflammatory factors and neurotransmitters, further contributing to its analgesic and antipruritic effects.[4]

The defining characteristic of HSK-21542's mechanism is its peripheral restriction. Earlier generations of KOR agonists that could penetrate the CNS were found to produce intolerable side effects such as sedation, dysphoria, and hallucinations, which ultimately halted their clinical development.[5] By being engineered to have minimal brain penetration, HSK-21542 avoids the activation of central KORs, thereby decoupling the desired peripheral therapeutic effects from the undesirable central side effects. This targeted mechanism represents a sophisticated approach to opioid pharmacology, building on the lessons learned from the failures of both MOR agonists and centrally-acting KOR agonists. It is not merely an incremental improvement but a strategic redesign aimed at creating a "clean" therapeutic agent by solving the central safety problem that has long plagued the development of potent analgesics.

In Vitro Characterization and Potency

Comprehensive in vitro studies have validated the high potency, selectivity, and unique binding kinetics of HSK-21542, establishing its superiority over other KOR agonists like CR845 (difelikefalin).

In competitive radioligand binding assays, HSK-21542 demonstrated a strong ability to displace the non-selective opioid ligand $[^3H]$diprenorphine from KORs. It exhibited a half-maximal inhibitory concentration (IC50​) of 0.54 nM. This indicates a higher binding affinity than the comparator KOR agonist CR845, which had an IC50​ of 1.16 nM under the same conditions.[16]

Functional assays measuring the drug's biological effect revealed even more profound potency. In HEK-293 cells expressing human KOR, HSK-21542 potently inhibited forskolin-induced cyclic AMP (cAMP) accumulation, a downstream marker of KOR activation. It did so with a half-maximal effective concentration (EC50​) of just 2.41 pM (picomolar). This level of potency is exceptional, being 12.4-fold greater (i.e., a lower concentration is needed) than that of CR845 and 747-fold greater than that of the reference KOR agonist U69593.[16]

Binding kinetics studies provided further insight into its interaction with the receptor. HSK-21542 was found to have a dissociation constant (Kd​) of 0.068 nM, again indicating very high affinity.[16] Furthermore, it exhibited a receptor-ligand dissociation half-life (

t1/2​) of 90.6 minutes. This is significantly longer than the 42.0-minute half-life observed for CR845, suggesting that HSK-21542 forms a more durable complex with the KOR, which may contribute to a more sustained pharmacological effect in vivo.[16]

The selectivity of HSK-21542 was confirmed through extensive screening against a broad panel of 85 other receptors, ion channels, and enzymes, including the closely related MOR and delta-opioid receptors (DOR). At a high concentration of 10 µM, no significant off-target activity was observed, with the minor exception of a 47% inhibition at the cannabinoid CB1 receptor, an effect unlikely to be clinically relevant at therapeutic concentrations. This confirms that HSK-21542 is a highly specific KOR agonist.[16]

III. Preclinical Evidence of Efficacy and Safety

Antinociceptive and Antipruritic Effects in Animal Models

An extensive preclinical program in various animal models provided robust proof-of-concept for HSK-21542's dual therapeutic activities. The drug demonstrated significant and dose-dependent antinociceptive (analgesic) effects across a spectrum of pain types. This included models of visceral pain (acetic acid-induced writhing), acute inflammatory/postoperative pain (hindpaw incision model), and chronic neuropathic pain (chronic constriction injury model).[5] This broad efficacy suggests its potential utility in diverse clinical pain states.

When compared directly with the peripherally restricted KOR agonist CR845, HSK-21542 showed comparable analgesic efficacy at 15 minutes after administration. However, a key differentiating feature emerged in its duration of action. In the writhing test, HSK-21542 exhibited a long-lasting analgesic effect, with a median effective dose (ED50​) of 1.48 mg/kg still measurable 24 hours after a single administration.[5] This prolonged pharmacodynamic effect, despite a short plasma half-life, suggests a durable engagement with the target receptor, potentially allowing for less frequent dosing and more sustained relief in a clinical setting.

In addition to its analgesic properties, HSK-21542 demonstrated powerful antipruritic (anti-itch) activity. In a mouse model where itching was induced by compound 48/80, HSK-21542 effectively suppressed itch-related behaviors.[5] The mechanism of action for both the analgesic and antipruritic effects was confirmed to be KOR-mediated, as the administration of nor-binaltorphimine, a selective KOR antagonist, effectively reversed these therapeutic effects.[5]

Validation of Peripheral Selectivity and CNS Safety

The foundational safety principle of HSK-21542—its peripheral restriction—was rigorously validated in preclinical studies. In vivo measurements confirmed its minimal ability to penetrate the blood-brain barrier (BBB), yielding an extremely low brain-to-plasma concentration ratio of 0.001.[5]

This physical restriction from the CNS translated directly into a superior safety profile. In animal studies designed to detect central effects, HSK-21542 showed only weak central antinociception in the hot-plate test, a model that requires CNS action.[5] It also had minimal impact on the locomotor activity of mice, indicating a lack of sedative effects.[5] Most critically, and in stark contrast to traditional MOR opioids, HSK-21542 did not cause any respiratory depression, even at high doses.[4] Further preclinical assessments concluded that HSK-21542 had no potential for abuse in rat models, reinforcing its favorable CNS safety profile.[19] This package of preclinical safety data provides compelling evidence that the drug's design successfully uncouples peripheral efficacy from central toxicity.

Reproductive and Developmental Toxicity Profile

Given that conventional opioids are known to have toxicological impacts on reproduction and development, HSK-21542 was subjected to a comprehensive series of reproductive and developmental toxicity studies in rats and rabbits.[12] The results from these studies were overwhelmingly positive and further solidified its favorable safety profile.

HSK-21542 was found to have no influence on male or female fertility or on early embryonic development in rats.[12] Furthermore, it did not demonstrate any significant manifestations of pre- or post-natal developmental toxicity.[12] In embryo-fetal development studies, a minor and non-significant increase in the incidence of fetuses with incomplete ossification of a thoracic vertebral centrum was noted in rats at a high dose (4 mg/kg/day), and a minor impact on bone ossification was seen in rabbit fetuses.[12] However, these findings were observed at exposures far exceeding those intended for human use. The no-observed-adverse-effect-level (NOAEL) in rats corresponded to a plasma exposure that was 82.3 times higher than the therapeutic exposure in humans, indicating a very wide safety margin and low risk of teratogenicity.[12]

IV. Clinical Pharmacology and Pharmacokinetics in Humans

Human Pharmacokinetic Profile (ADME)

The clinical pharmacology of HSK-21542 has been well-characterized through a series of Phase I studies in healthy volunteers (e.g., NCT04213196) and a dedicated mass balance study (NCT05835934).[13] These studies have revealed an exceptionally "clean" and predictable pharmacokinetic (PK) profile, a significant asset for a drug intended for diverse and often fragile patient populations.

Following intravenous administration, HSK-21542 exhibits dose-linear pharmacokinetics. Across a dose range of 0.2 to 3.375 µg/kg, both the peak plasma concentration (Cmax​) and the area under the concentration-time curve (AUC) increased proportionally with the dose.[21] The drug is eliminated from the body relatively quickly, with a short plasma elimination half-life (

t1/2​) of approximately 1.5 hours.[21]

A human mass balance study using radiolabeled $[^{14}C]$HSK21542 provided definitive insights into its absorption, distribution, metabolism, and excretion (ADME) properties.[13] The study confirmed that HSK-21542 undergoes minimal metabolism

in vivo. The unchanged parent drug was found to be the predominant circulating substance in plasma, accounting for 92.17% of the total radioactivity AUC. It was also the only major radioactive chemical identified in both urine (100% of radioactivity) and feces (93.53% of radioactivity), indicating that metabolites are very minor components.[13] This lack of significant metabolism is a key advantage, as it minimizes the risk of drug-drug interactions (DDIs) mediated by common metabolic pathways (e.g., cytochrome P450 enzymes) and reduces PK variability related to genetic differences in patient metabolism.

The total recovery of the administered radioactive dose was 81.89% over a 240-hour collection period. Excretion was split between two primary routes: 46.30% of the dose was recovered in urine and 35.60% in feces. This suggests that renal excretion is the principal elimination pathway, with biliary/fecal excretion serving as a secondary pathway.[13] The measured blood-to-plasma ratio of total radioactivity ranged from 0.46 to 0.54, indicating that the drug does not significantly partition into red blood cells.[13]

Pharmacokinetic Modeling in Special Populations

Recognizing that HSK-21542 would be used in patients with compromised organ function (e.g., postoperative patients, those with renal failure), the developer, Haisco Pharmaceutical, employed a modern, model-informed drug development strategy. A physiologically-based pharmacokinetic (PBPK) model was developed to proactively predict drug exposure in key special populations.[24]

The PBPK model predicted that systemic exposure (AUC) to HSK-21542 would be elevated in certain groups compared to healthy adults. Specifically, the model forecasted a 52% to 71% increase in AUC in patients with moderate to severe renal impairment, a 46% to 77% increase in those with mild to severe hepatic impairment, and a 45% to 85% increase in elderly individuals (aged 65-95 years).[24] This foresight allowed the company to anticipate the need for dose adjustments and to design subsequent clinical trials with appropriate dosing regimens for these vulnerable populations. In fact, this PBPK model was used to support dose selection in the actual clinical trials for patients with renal and hepatic impairment (CTR20201702 and CTR20211940), demonstrating a sophisticated approach to mitigating risk and optimizing the drug's development path.[24]

Conversely, the model predicted a potential decrease in systemic exposure, ranging from 20% to 37%, in pediatric patients (aged 0-17 years). This finding is critical for future development, as it highlights the need for careful dose-finding studies in this population to avoid potential treatment failure due to under-dosing.[24] The predictive accuracy of the model was later validated when observed drug exposure in elderly patients in clinical trials closely matched the model's predictions.[24]

V. Clinical Efficacy in Postoperative Pain Management

Phase II Trial in Laparoscopic Surgery (NCT04424251)

The clinical journey of HSK-21542 in pain management began with a Phase II, randomized, placebo-controlled, two-stage trial designed to identify the optimal dosing regimen for postoperative analgesia.[19] The study enrolled patients undergoing elective laparoscopic abdominal surgery. Stage 1 of the trial involved ascending dose cohorts to establish safety and a preliminary efficacy signal. Stage 2 then focused on comparing two promising doses, 0.5 µg/kg and 1.0 µg/kg of HSK-21542, against a placebo. The study drug was administered intravenously at 0, 8, and 16 hours following surgery.[19]

The primary endpoint was the time-weighted summed pain intensity difference over 24 hours (SPID0-24h). While the pooled analysis of this endpoint showed a numerical trend favoring the 1.0 µg/kg dose over placebo, it did not achieve statistical significance (P=0.114).[19] However, a statistically significant efficacy signal was detected in a key secondary endpoint. The least squares (LS) mean difference of pain intensity differences (PID) was significantly greater in the HSK-21542 1.0 µg/kg group compared to the placebo group (

P=0.020).[19]

Based on this clear signal of analgesic activity and a safety profile that was comparable to placebo, the dosing regimen of 1.0 µg/kg was deemed to have an acceptable efficacy and was recommended for advancement into the larger, pivotal Phase III trials.[19]

Pivotal Phase III Trials (HSK21542-301 & HSK21542-303)

The efficacy and safety of HSK-21542 for postoperative pain were definitively established in two large, multicenter, randomized, double-blind, pivotal Phase III trials conducted in China in patients experiencing moderate-to-severe pain after abdominal surgery.[6]

The first trial, HSK21542-301 (NCT04738357), was a placebo-controlled study. It successfully met its primary endpoint, demonstrating the superiority of HSK-21542 over placebo. The LS mean for the SPID0-24h was significantly better for the HSK-21542 group compared to the placebo group (-39.1 vs -27.4, respectively; P<0.001).[4]

The second and more comprehensive trial, HSK21542-303 (NCT05390905), employed a three-arm design, comparing HSK-21542 (at the 1.0 µg/kg dose) against both placebo and an active comparator, tramadol (50 mg).[25] This trial successfully replicated the finding of superiority over placebo, with an LS mean SPID0-24h of -64.0 for HSK-21542 versus -45.9 for placebo (

P<0.001).[4] Critically, the trial also met its key objective of demonstrating

non-inferiority to tramadol, a widely used analgesic. The LS mean difference between HSK-21542 and tramadol was -1.1, which fell within the predefined non-inferiority margin.[4] This result established HSK-21542 as an effective analgesic with potency comparable to a standard-of-care agent.

Trial ID	Primary Endpoint	Comparator	HSK-21542 (LS Mean ± SE)	Comparator (LS Mean ± SE)	Result	P-value
HSK21542-301	SPID0-24h	Placebo	-39.1 ± 1.88	-27.4 ± 1.89	Superiority	<0.001
HSK21542-303	SPID0-24h	Placebo	-64.0 ± 2.25	-45.9 ± 2.25	Superiority	<0.001
HSK21542-303	SPID0-24h	Tramadol 50 mg	-64.0 ± 2.25	N/A	Non-inferiority	Met

Table 1: Summary of Primary Efficacy Outcomes in Phase III Postoperative Pain Trials. Data sourced from.[4] SPID0-24h = Sum of Pain Intensity Differences at rest within 0–24 h. LS = Least Squares. SE = Standard Error.

Emerging Data in Orthopedic Surgery

Building upon the successful outcomes in abdominal surgery, Haisco is expanding the clinical program for HSK-21542 into other areas of high unmet need. The company has initiated a Phase III clinical trial designed to enroll 405 patients in China to evaluate the efficacy and safety of HSK-21542 for analgesia after orthopedic surgery.[3] This is a logical and commercially significant expansion, as orthopedic procedures are often highly traumatic and associated with significant postoperative inflammatory pain. The demand for potent, effective, and non-addictive analgesics that can avoid the risks of traditional opioids (respiratory depression, addiction) and non-steroidal anti-inflammatory drugs (gastrointestinal damage, cardiovascular risks) is particularly high in this patient population.[3]

VI. Clinical Efficacy in Chronic Kidney Disease-Associated Pruritus (CKD-aP)

Phase II Trial in Hemodialysis Patients (NCT04470154)

HSK-21542 was evaluated for the treatment of uremic pruritus in a multi-center, randomized, double-blind, placebo-controlled Phase II clinical trial involving patients on maintenance hemodialysis who suffered from moderate-to-severe CKD-aP.[10] The trial was structured in two stages. Stage 1 was a short-term (1-week), multiple ascending dose study (0.05 µg/kg to 0.80 µg/kg) designed to assess safety and pharmacokinetics and to identify the optimal doses for further investigation.[28]

Based on the findings from Stage 1, Stage 2 was a 12-week treatment period where patients were randomized in a 1:1:1 ratio to receive either HSK-21542 at a dose of 0.3 µg/kg, HSK-21542 at a dose of 0.6 µg/kg, or a matching placebo. The study medication was administered intravenously three times per week after each dialysis session.[10] The primary efficacy endpoint for the trial was the change from baseline in the weekly mean of the Worst Itching Intensity Numerical Rating Scale (WI-NRS) score at week 12.[11]

Impact on Itch Intensity and Quality of Life

The results from the 12-week Stage 2 trial revealed a notable and somewhat unexpected dose-response relationship. The lower dose of 0.3 µg/kg HSK-21542 demonstrated superior efficacy compared to both placebo and the higher 0.6 µg/kg dose. At week 12, patients in the 0.3 µg/kg group experienced the largest mean reduction in their WI-NRS score from baseline, with a change of -3.40 points. This was numerically greater than the reduction seen in the placebo group (-2.94 points) and significantly better than the reduction in the 0.6 µg/kg group (-2.21 points).[10]

This pattern was also reflected in the responder analysis. The percentage of patients achieving a clinically meaningful improvement (defined as a reduction of 3 points or more in their WI-NRS score) was highest in the 0.3 µg/kg group at 62.1%. This was substantially better than the 44.4% response rate in the placebo group and the 37.0% rate in the 0.6 µg/kg group.[10] Another report, likely from a pooled or final dataset, indicated an even more pronounced and statistically significant difference, with 51.0% of HSK-21542 patients achieving this endpoint compared to only 24.2% of placebo patients (

P<0.001).[31]

The benefits of the 0.3 µg/kg dose extended to improvements in quality of life. This group showed more significant improvements in the Skindex-16 and Skindex-10 scores, which are validated instruments for measuring the impact of skin conditions on a patient's life, compared to the placebo group. Similar positive trends favoring the 0.3 µg/kg dose were also observed in the 5-D Itch Scale scores.[4]

The observation that the lower 0.3 µg/kg dose was more effective than the higher 0.6 µg/kg dose suggests a non-linear, or possibly bell-shaped, dose-response curve for this indication. This is a crucial finding, as it deviates from the typical "more is better" pharmacological principle. This phenomenon could be due to complex biological mechanisms, such as KOR receptor downregulation or desensitization occurring more rapidly at higher drug concentrations, leading to a blunting of the therapeutic effect (tachyphylaxis). This underscores the critical importance of the careful dose-finding work conducted in the Phase II study, which successfully identified the optimal therapeutic dose and prevented the potential failure of a Phase III trial that might have otherwise tested a less effective, higher dose. Ultimately, the trial concluded that the 0.3 µg/kg dose of HSK-21542 offered the best balance of efficacy and safety for reducing pruritus and improving quality of life in hemodialysis patients.[4]

VII. Comprehensive Safety and Tolerability Profile

Adverse Event Profile Across Clinical Programs

HSK-21542 has demonstrated a consistent and favorable safety and tolerability profile throughout its extensive clinical development program, from initial studies in healthy volunteers to large-scale Phase III trials in patient populations.[4]

In the first-in-human Phase I study (NCT04213196) conducted in healthy volunteers, the drug was well tolerated. The most frequently reported treatment-emergent adverse event (TEAE) was transient paresthesia (a sensation of tingling or numbness), which occurred in 42% of subjects receiving the drug.[21] The vast majority of AEs were mild (Grade 1), with only 4% of subjects experiencing a Grade 2 event. Importantly, no serious adverse events (SAEs) were observed, and no participants withdrew from the study due to AEs.[21] A transient, asymptomatic increase in prolactin levels was also noted, which is a known on-target pharmacodynamic effect of KOR agonism and was not considered clinically adverse.[21]

In the Phase II postoperative pain trial (NCT04424251), the safety profile of HSK-21542 was comparable to that of placebo. The most common TEAEs reported in the HSK-21542 group were fever, nausea, and vomiting, but their incidence was similar to that observed in the placebo group, suggesting they were likely related to the surgery and anesthesia rather than the study drug.[19] Similarly, in the Phase II pruritus trial (NCT04470154), while the overall incidence of TEAEs was higher in the HSK-21542 groups compared to placebo, all reported events were mild to moderate in severity (Grade 1 or 2).[29] One report from this program noted that dizziness and hypotension were more common in the HSK-21542 group than in the placebo group.[31]

Comparative Safety Analysis

The pivotal Phase III pain trial, HSK21542-303, provided the most robust comparative safety data. In this trial, the overall safety profile of HSK-21542 was found to be comparable to that of placebo.[4]

A critical and clinically significant finding was the superior gastrointestinal (GI) safety of HSK-21542 when compared to the active comparator, tramadol. Patients receiving HSK-21542 experienced fewer GI-related adverse events, such as nausea and vomiting, than those receiving tramadol.[4] This is a major differentiating factor, as opioid-induced GI side effects are a common cause of patient dissatisfaction, non-compliance, and delayed recovery after surgery.

The incidence of severe adverse events was consistently low across the Phase III program. The rate of Grade ≥3 TEAEs was 5.9% in the HSK21542-301 trial and even lower at 2.3% in the HSK21542-303 trial, further underscoring the drug's excellent tolerability.[4]

Adverse Event	HSK-21542 (n=129)	Tramadol (n=129)	Placebo (n=129)
Nausea	Data not specified	Data not specified	Data not specified
Vomiting	Data not specified	Data not specified	Data not specified
Any GI-related AE	Fewer than Tramadol	Higher than HSK-21542	N/A
Dizziness	Data not specified	Data not specified	Data not specified
Any Grade ≥3 TEAE	2.3%	Data not specified	Data not specified

Table 2: Summary of Key Safety Findings in Phase III Pain Trial HSK21542-303. Note: Specific incidence rates for individual AEs were not available in the provided materials, but comparative findings were reported. Data sourced from.[4]

Assessment of Abuse Potential and CNS-Related Events

The fundamental design principle of HSK-21542—its peripheral restriction—was intended to eliminate the CNS-mediated side effects that plague other opioid classes. The clinical safety data strongly support the success of this strategy. Preclinical studies in rats had already indicated that the drug lacked abuse potential.[19]

Throughout the extensive clinical trial program, there have been no reports of the most serious opioid-related CNS adverse events. There is no mention of respiratory depression, the most life-threatening side effect of MOR agonists.[4] Likewise, there has been no safety signal for the dysphoria, hallucinations, or other severe psychiatric events that are characteristic of centrally-acting KOR agonists.[4] This clean CNS profile is the drug's primary and most significant safety advantage, positioning it as a much safer alternative to conventional opioid analgesics.

VIII. Regulatory Status and Competitive Landscape

Developer and Regulatory Milestones

HSK-21542 was discovered and developed by Sichuan Haisco Pharmaceutical Co., Ltd., a Chengdu-based subsidiary of the larger Haisco Pharmaceutical Group Co., Ltd..[1] The drug is marketed under the trade name

Anrikefon.[1]

A landmark achievement for the company and the drug occurred on May 12-13, 2025, when the parenteral (intravenous) formulation of Anrikefon received regulatory approval in China from the National Medical Products Administration (NMPA) for the treatment of postoperative pain.[1]

In addition to this approval, HSK-21542 is in the preregistration phase for the indication of pruritus in China.[1] The company is also exploring its use for postoperative nausea and vomiting (PONV), with a clinical trial for this indication having been completed.[1]

A significant strategic advantage for Anrikefon in the Chinese market is its regulatory classification. It is the first opioid analgesic in China to be designated as a "white prescription," meaning it is not managed under the strict regulations for narcotic drugs. This drastically reduces administrative burdens for hospitals and physicians, making it easier to prescribe, promote, and use, particularly in grassroots-level medical institutions and for rapid application after surgery.[3]

Competitive Analysis: HSK-21542 vs. Difelikefalin (Korsuva/Kapruvia)

The most direct competitor to HSK-21542 is difelikefalin (brand names Korsuva, Kapruvia), a peripherally restricted KOR agonist developed by Cara Therapeutics.[34] While both drugs share the same mechanism of action, their development paths, approved indications, and market positioning show key strategic differences.

• Target and Potency: Both are selective, peripherally restricted KOR agonists.[4] However, preclinical in vitro data suggests that HSK-21542 is significantly more potent than CR845 (the research name for difelikefalin) at the KOR and has a longer receptor dissociation half-life.[16]
• Primary Indication and Geography: The two companies have pursued different initial market entry strategies. Difelikefalin (IV) was first approved in the USA (August 2021) and the EU (April 2022) for the treatment of moderate-to-severe CKD-associated pruritus in adult patients undergoing hemodialysis.[34] In contrast, HSK-21542 (IV) was first approved in China for postoperative pain, with CKD-aP as its primary follow-on indication in that market.[1]
• Pipeline and Formulation: Both companies are working to expand the use of their drugs. Haisco is actively pursuing label expansions for HSK-21542 in orthopedic pain and PONV.[1] Cara Therapeutics has invested in developing an oral formulation of difelikefalin to expand its use beyond the IV-only setting of dialysis clinics. However, this effort has faced significant challenges, with oral difelikefalin failing to meet the primary endpoint in a Phase 2 trial for atopic dermatitis.[35] The development of a stable and effective oral peptide-based KOR agonist remains a major technical hurdle.

Feature	HSK-21542 (Anrikefon)	Difelikefalin (Korsuva/Kapruvia)
Developer	Haisco Pharmaceutical Group	Cara Therapeutics
Chemical Class	Synthetic Peptide	Synthetic Peptide (Tetrapeptide)
Primary Approved Indication	Postoperative Pain	Chronic Kidney Disease-Associated Pruritus (CKD-aP)
Route of Administration	Intravenous (IV)	Intravenous (IV)
Geographic Approval(s)	China	USA, European Union
Key Secondary Indication	CKD-aP (China, preregistration), Orthopedic Pain (Phase III)	Postoperative Pain (less focus)
Key Differentiating Feature	Approved as non-narcotic in China; Higher in vitro potency	First-in-class approval for CKD-aP in US/EU; Oral formulation development has faced setbacks

Table 3: Comparative Profile of HSK-21542 (Anrikefon) vs. Difelikefalin (Korsuva). Data sourced from.[1]

IX. Strategic Analysis and Future Outlook

Assessment of Therapeutic Niche and Unmet Needs

HSK-21542 (Anrikefon) is strategically positioned to address a critical and long-standing unmet need in global medicine: the demand for potent analgesics that are devoid of the abuse potential, addiction risk, and severe CNS side effects associated with traditional opioids. The robust Phase III data demonstrating non-inferiority to tramadol, coupled with a superior gastrointestinal safety profile, makes it a highly attractive alternative in the acute postoperative setting.[3] Its use could be particularly valuable in surgeries where rapid recovery of bowel function is a priority and in patients for whom traditional opioids are contraindicated or poorly tolerated.

The unique regulatory status of Anrikefon in China as a "white prescription" (non-narcotic) drug provides a powerful commercial advantage in that market. By removing the significant administrative and logistical hurdles associated with controlled substances, Haisco has paved the way for wider and more rapid adoption by hospitals and clinics across the country.[3]

In the therapeutic area of pruritus, HSK-21542 offers a targeted, mechanism-based treatment for a highly distressing and intractable symptom that severely impacts the quality of life of hemodialysis patients. In this niche, it will compete directly with the established first-in-class agent, difelikefalin.

Future Development Trajectory

Haisco Pharmaceutical is pursuing a clear and logical strategy for the life-cycle management and value creation of HSK-21542, focused on expanding its use into new indications and patient populations.

• Indication Expansion: The ongoing Phase III trial in orthopedic pain represents the most significant near-term growth opportunity, targeting a large market with a high need for safe and effective analgesia.[3] Furthermore, the completion of a clinical trial for postoperative nausea and vomiting (PONV) suggests that another label expansion may be on the horizon, which would further solidify its role in the perioperative setting.[1]
• Special Populations: The company has shown a commitment to thoroughly characterizing the drug's use across the full spectrum of potential patients. The proactive PBPK modeling and dedicated clinical trials in patients with renal impairment (e.g., NCT06238388) demonstrate a sophisticated approach to defining its use in vulnerable populations.[24] The PBPK model's prediction of lower drug exposure in pediatric patients is a key finding that signals the need for future pediatric trials with carefully designed dose-finding components to ensure efficacy and safety in this group.[24]
• Formulation Development: All currently available data pertains to the parenteral (IV) formulation of HSK-21542. The significant technical challenges and clinical trial setbacks faced by Cara Therapeutics in its attempt to develop an oral version of difelikefalin highlight that creating a successful oral formulation of a peptide-based KOR agonist is a non-trivial endeavor.[35] There is currently no public information to suggest that Haisco is pursuing an oral route for HSK-21542. This represents both a potential future opportunity for significant market expansion and a major technical hurdle that would need to be overcome.

Expert Recommendations and Concluding Remarks

HSK-21542 (Anrikefon) stands out as a prime example of successful rational drug design, where a deep understanding of the pharmacology of a target class has been leveraged to systematically engineer out the historical liabilities that have plagued it. Its molecular structure, mechanism of action, and pharmacokinetic profile have been optimized to deliver peripheral therapeutic effects while minimizing central toxicity.

The drug's initial approval in China for postoperative pain is supported by a strong and compelling Phase III data package, demonstrating superiority over placebo and non-inferiority to an active standard-of-care, tramadol, but with a clinically meaningful safety advantage. This provides a solid foundation for commercial success and establishes Anrikefon as a valuable new tool for pain management. The well-defined development strategy, with active programs in CKD-aP, orthopedic pain, and PONV, indicates a clear path toward maximizing the asset's clinical and commercial potential.

Several key strategic questions will define the future trajectory of HSK-21542:

1. Global Expansion: Can Haisco successfully navigate the complex regulatory landscapes of the United States and Europe to replicate its approval success outside of China?
2. Competitive Positioning: In the CKD-aP market, will its efficacy and safety profile be sufficiently differentiated to effectively compete with the already-established difelikefalin?
3. Future Innovation: Is an oral formulation of HSK-21542 technically feasible, and is it part of the company's long-term development roadmap?

In conclusion, HSK-21542 is a highly promising new therapeutic agent with a well-defined mechanism, a robust clinical data package in its initial indications, and a clear strategic vision for its future. It has the potential to become a new standard-of-care option for the management of moderate-to-severe acute pain and chronic pruritus, particularly in settings where safety, tolerability, and the avoidance of CNS effects are paramount. Its journey through global markets will be a key test case for the commercial viability of the next generation of peripherally acting, non-addictive analgesics.

Works cited

1. Anrikefon - Sichuan Haisco Pharmaceutical - AdisInsight, accessed August 13, 2025, https://adisinsight.springer.com/drugs/800056188
2. Haisco Pharmaceutical Group Co., Ltd. - Drug pipelines, Patents, Clinical trials - Synapse, accessed August 13, 2025, https://synapse.patsnap.com/organization/8a4752a4e5e1fab8ab074b148eba6558
3. Haisco Pharmaceutical Group (002653): Initiating Phase III Clinical Trial of HSK21542 Injection for Pain Relief After Orthopedic Surgery, accessed August 13, 2025, https://news.futunn.com/en/post/59904725/haisco-pharmaceutical-group-002653-initiation-of-phase-iii-clinical-trial
4. Chemical structures of HSK21542 (A) and CR845 (B). - ResearchGate, accessed August 13, 2025, https://www.researchgate.net/figure/Chemical-structures-of-HSK21542-A-and-CR845-B_fig1_356259505
5. (PDF) Antinociceptive and Antipruritic Effects of HSK21542, a Peripherally-Restricted Kappa Opioid Receptor Agonist, in Animal Models of Pain and Itch - ResearchGate, accessed August 13, 2025, https://www.researchgate.net/publication/356259505_Antinociceptive_and_Antipruritic_Effects_of_HSK21542_a_Peripherally-Restricted_Kappa_Opioid_Receptor_Agonist_in_Animal_Models_of_Pain_and_Itch
6. HSK21542 in patients with postoperative pain: two phase 3, multicentre, double-blind, randomized, controlled trials - ResearchGate, accessed August 13, 2025, https://www.researchgate.net/journal/Nature-Communications-2041-1723/publication/392069557_HSK21542_in_patients_with_postoperative_pain_two_phase_3_multicentre_double-blind_randomized_controlled_trials/links/68328529026fee1034fb4422/HSK21542-in-patients-with-postoperative-pain-two-phase-3-multicentre-double-blind-randomized-controlled-trials.pdf?origin=scientificContributions
7. HSK21542 in patients with postoperative pain: two phase 3, multicentre, double-blind, randomized, controlled trials - PubMed, accessed August 13, 2025, https://pubmed.ncbi.nlm.nih.gov/40413233/
8. HSK21542 in patients with postoperative pain: two phase 3, multicentre, double-blind, randomized, controlled trials - PMC - PubMed Central, accessed August 13, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC12103582/
9. May 2025 Drug Approval Wave: From KRAS-Targeted Combinations to Novel ADCs in NSCLC - Patsnap Synapse, accessed August 13, 2025, https://synapse.patsnap.com/blog/may-2025-drug-approval-wave-from-kras-targeted-combinations-to-novel-adcs-in-nsclc
10. Efficacy and safety of HSK21542 for pruritus management in hemodialysis patients: a multicenter, randomized, double-blind, placebo-controlled trial - PubMed Central, accessed August 13, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC12235262/
11. (PDF) Efficacy and safety of HSK21542 for pruritus management in hemodialysis patients: a multicenter, randomized, double-blind, placebo-controlled trial - ResearchGate, accessed August 13, 2025, https://www.researchgate.net/publication/392994133_Efficacy_and_safety_of_HSK21542_for_pruritus_management_in_hemodialysis_patients_a_multicenter_randomized_double-blind_placebo-controlled_trial
12. Anrikefon - Drug Targets, Indications, Patents - Patsnap Synapse, accessed August 13, 2025, https://synapse.patsnap.com/drug/bd865e5181284bcb98177b5b93580127
13. Sichuan Haisco Pharmaceutical Co., Ltd. - Drug pipelines, Patents, Clinical trials - Synapse, accessed August 13, 2025, https://synapse.patsnap.com/organization/984367240d4cfb3268efba14decfb050
14. HSK21542 | CAS# | Opioid receptor agonist - MedKoo Biosciences, accessed August 13, 2025, https://www.medkoo.com/products/50674
15. Anrikefon (HSK21542) | Kappa Opioid Receptor Agonist | MedChemExpress, accessed August 13, 2025, https://www.medchemexpress.com/anrikefon.html
16. Antinociceptive and Antipruritic Effects of HSK21542, a Peripherally-Restricted Kappa Opioid Receptor Agonist, in Animal Models of Pain and Itch - PubMed Central, accessed August 13, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC8635029/
17. Haisco Pharma's Cat1 drug under trial review for postoperative analgesia - source, accessed August 13, 2025, https://source.gbihealth.com.cn/news/detail?id=2049388&utm_source=official
18. Antinociceptive and Antipruritic Effects of HSK21542, a Peripherally-Restricted Kappa Opioid Receptor Agonist, in Animal Models of Pain and Itch - Bohrium, accessed August 13, 2025, https://www.bohrium.com/paper-details/antinociceptive-and-antipruritic-effects-of-hsk21542-a-peripherally-restricted-kappa-opioid-receptor-agonist-in-animal-models-of-pain-and-itch/813237892649320449-6781
19. Efficacy and safety of peripherally-restricted κ-opioid receptor agonist-HSK21542 for postoperative analgesia in patients undergoing laparoscopic abdominal surgery: a randomized, placebo-controlled phase 2 trial - Frontiers, accessed August 13, 2025, https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2025.1604790/epub
20. Efficacy and safety of peripherally-restricted κ-opioid receptor agonist-HSK21542 for postoperative analgesia in patients undergoing laparoscopic abdominal surgery: a randomized, placebo-controlled phase 2 trial | Scilit, accessed August 13, 2025, https://www.scilit.com/publications/d99fda64efa8fbf1e59094b9baf586ad
21. Phase I clinical trial evaluating the safety, tolerance, pharmacokinetics and pharmacodynamics of HSK21542 injection in healthy volunteers - PubMed, accessed August 13, 2025, https://pubmed.ncbi.nlm.nih.gov/39397291/
22. Study Details | Safety, Tolerability and Pharmacokinetics of HSK21542 in Healthy Volunteers | ClinicalTrials.gov, accessed August 13, 2025, https://clinicaltrials.gov/study/NCT04213196
23. Sichuan Haisco Pharmaceutical Co., Ltd. - Drug pipelines, Patents, Clinical trials - Synapse, accessed August 13, 2025, https://synapse-patsnap-com.libproxy1.nus.edu.sg/organization/984367240d4cfb3268efba14decfb050
24. Model informed drug development: HSK21542 PBPK model supporting dose decisions in specific populations - PubMed, accessed August 13, 2025, https://pubmed.ncbi.nlm.nih.gov/38599505/
25. HSK21542 / Haisco - LARVOL DELTA, accessed August 13, 2025, https://delta.larvol.com/Products/?ProductId=36bd0a02-d735-4898-9b1b-7ce039c5b269
26. HSK21542 in patients with postoperative pain: two phase 3, multicentre, double-blind, randomized, controlled trials - ResearchGate, accessed August 13, 2025, https://www.researchgate.net/publication/392069557_HSK21542_in_patients_with_postoperative_pain_two_phase_3_multicentre_double-blind_randomized_controlled_trials
27. Study Details | A Clinical Trial Evaluating the Efficacy and Safety of ..., accessed August 13, 2025, https://clinicaltrials.gov/study/NCT05390905
28. A Study Evaluating the Safety, Pharmacokinetics, and Efficacy of HSK21542 Injection in Subjects Undergoing Hemodialysis | ClinicalTrials.gov, accessed August 13, 2025, https://clinicaltrials.gov/study/NCT04470154
29. Safety and effectiveness of HSK21542 for hemodialysis patients: a multiple ascending dose study - PubMed Central, accessed August 13, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10590914/
30. Safety and effectiveness of HSK21542 for hemodialysis patients: a multiple ascending dose study - Frontiers, accessed August 13, 2025, https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2023.1203642/full
31. Kidney Week - Abstract Details (2024) - American Society of Nephrology, accessed August 13, 2025, https://www.asn-online.org/education/kidneyweek/2024/program-abstract.aspx?controlId=4165465
32. Likelihood of Approval and Phase Transition Success Rate Model – HSK-21542 in Post-Operative Pain - GlobalData, accessed August 13, 2025, https://www.globaldata.com/store/report/hsk-21542-in-post-operative-pain-loa-innovation-and-trend-analysis-2/
33. Liaoning Haisco Pharmaceutical Co., Ltd. - Drug pipelines, Patents, Clinical trials - Synapse, accessed August 13, 2025, https://synapse.patsnap.com/organization/a1260a841e59172d9033938afd7973ea
34. Difelikefalin: First Approval - ResearchGate, accessed August 13, 2025, https://www.researchgate.net/publication/355572832_Difelikefalin_First_Approval
35. Kappa opioid agonists in the treatment of itch: just scratching the surface? - PMC - PubMed Central, accessed August 13, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10720604/
36. Study Details | Metabolism and Excretory of HSK21542 in Maintenance Hemodialysis Patients | ClinicalTrials.gov, accessed August 13, 2025, https://clinicaltrials.gov/study/NCT06238388