Comprehensive Report on KN-057 (Armocibart): A Novel TFPI-Inhibiting Monoclonal Antibody for Hemophilia

Executive Summary

KN-057, also known under the proposed International Nonproprietary Name (INN) Armocibart, is an investigational monoclonal antibody developed by Suzhou Alphamab Biotechnology Co., Ltd. It functions by inhibiting Tissue Factor Pathway Inhibitor (TFPI), a natural anticoagulant, thereby promoting coagulation.[1] This mechanism is particularly relevant for treating hemophilia A and B, including patients who have developed inhibitors to standard factor replacement therapies, as the action of KN-057 is independent of the deficient or inhibited clotting factors VIII or IX.[3] Currently, KN-057 is advancing through late-stage clinical development, with multiple Phase 3 trials underway in China and a Phase 2 trial completed.[1] Administered subcutaneously, early clinical data suggests a favorable safety profile, a pharmacokinetic profile supporting once-weekly dosing, and positive pharmacodynamic effects on thrombin generation.[5] Highlighting its potential to address a significant unmet medical need, KN-057 has received Orphan Drug Designation from the U.S. Food and Drug Administration (FDA) for hemophilia A.[2] This report synthesizes available preclinical rationale, clinical trial details, pharmacokinetic and pharmacodynamic profiles, safety information, regulatory status, and intellectual property pertaining to KN-057.

The development of KN-057 for both hemophilia A and B, including cohorts with inhibitors [1], positions it to address substantial unmet needs. Inhibitor development is a major complication in hemophilia management, significantly limiting treatment efficacy and options.[13] A therapeutic agent like KN-057, which functions independently of the inhibited factor, offers a promising alternative for this difficult-to-treat patient segment, potentially providing a universal prophylactic or treatment solution. Furthermore, the subcutaneous route of administration and a pharmacokinetic profile supporting once-weekly dosing [5] represent a considerable improvement in convenience and patient compliance over traditional, frequent intravenous factor replacement therapies.[13] This shift towards a less burdensome regimen could significantly enhance the quality of life for individuals with hemophilia. The U.S. FDA's granting of Orphan Drug Designation for hemophilia A [11] underscores the potential clinical importance of KN-057, reflecting regulatory acknowledgment of its promise and providing incentives that may expedite its development and availability.

1. Introduction to KN-057

KN-057 is an investigational therapeutic agent representing a novel approach to the management of hemophilia. Its development is centered on modulating the body's natural coagulation pathways to restore hemostasis in individuals with bleeding disorders.

It is important to note that the designation "KN-057" has appeared in literature for different investigational products. For instance, KEYNOTE-057 refers to a clinical trial for pembrolizumab in bladder cancer.[14] Another distinct investigational agent, also referred to as KN-057 in one source, is reportedly being developed for autoimmune diseases by targeting pro-inflammatory cytokines.[24] This report will focus exclusively on the monoclonal antibody KN-057 (Armocibart) developed by Suzhou Alphamab Biotechnology Co., Ltd. for the treatment of hemophilia by targeting TFPI, as this is the most consistently and substantially described entity in the available research materials.

1.1. Drug Identity and Nomenclature

KN-057 is identified as an investigational monoclonal antibody (mAb).[1] The proposed International Nonproprietary Name (INN) for KN-057 is Armocibart.[28] It is also referred to by internal development codes such as kn-057, kn 057, and kn057.[1] The intended route of administration for KN-057 is subcutaneous (SC) injection.[1]

The designation as a monoclonal antibody signifies a targeted biological therapy, distinct from traditional small molecule drugs or plasma-derived factor concentrates. The subcutaneous route of administration is a particularly noteworthy feature, as it offers the potential for improved patient convenience and self-administration, which is a significant advantage for chronic conditions like hemophilia that traditionally require frequent intravenous treatments.

1.2. Developer and Strategic Collaborations

KN-057 was independently developed by Suzhou Alphamab Biotechnology Co., Ltd., a company also referred to as Alphamab Oncology or Jiangsu Alphamab Biopharmaceuticals in various documents.[1] Alphamab Oncology's pipeline showcases a focus on innovative biologics, including single-domain antibodies, bispecific antibodies, and antibody-drug conjugates (ADCs), primarily in the field of oncology, but also extending to hematology with KN-057.[30] This background in complex biologic drug development underscores the company's R&D capabilities.

In September 2023, Suzhou Alphamab Biotechnology Co., Ltd. entered into a strategic cooperation agreement with Sichuan Yuanda Shuyang Pharmaceutical Co., Ltd., a wholly-owned subsidiary of Yuanda Life Sciences Group Co., Ltd. This agreement grants Sichuan Yuanda Shuyang Pharmaceutical the license for the Greater China rights of KN-057.[2] This partnership is a critical step for market access and commercialization within Greater China, leveraging local expertise and presence, and signals confidence in the asset from a regional partner.

1.3. Therapeutic Rationale: Addressing Unmet Needs in Hemophilia via TFPI Inhibition

Hemophilia A and hemophilia B are X-linked recessive bleeding disorders characterized by deficiencies in coagulation Factor VIII (FVIII) and Factor IX (FIX), respectively.[13] These deficiencies lead to impaired thrombin generation, resulting in an increased propensity for spontaneous and trauma-induced bleeding, particularly into joints and muscles, which can cause chronic pain and disability.

The current standard of care for severe hemophilia often involves prophylactic replacement of the deficient clotting factor. However, this approach has limitations, including the burden of frequent intravenous infusions and the significant risk of developing neutralizing alloantibodies, known as inhibitors, which render the factor replacement therapy ineffective.[13] Patients with inhibitors face considerable treatment challenges and often require more complex and costly bypassing agents.

Tissue Factor Pathway Inhibitor (TFPI) is a Kunitz-type serine protease inhibitor that functions as a crucial natural anticoagulant. Its primary role is to dampen the initiation phase of coagulation by inhibiting Factor Xa (FXa) and, in a FXa-dependent manner, the Tissue Factor-Factor VIIa (TF-FVIIa) complex.[3]

The therapeutic rationale for KN-057 is based on the principle of rebalancing hemostasis. By specifically inhibiting TFPI, KN-057 is designed to reduce the natural anticoagulant activity at the site of vascular injury. This disinhibition of the extrinsic coagulation pathway is expected to enhance the generation of FXa by the TF/FVIIa complex and subsequently increase thrombin generation, even in the absence or reduced activity of FVIII or FIX.[3] Because this mechanism of action does not depend on the presence of functional FVIII or FIX, KN-057 holds promise as a treatment for both hemophilia A and B, and importantly, for patients who have developed inhibitors to factor replacement therapies. This approach represents a shift from direct factor replacement to modulating the body's own coagulation system, potentially offering a more universally applicable and convenient therapeutic option.

2. Mechanism of Action

KN-057 exerts its procoagulant effect by targeting and neutralizing a key endogenous anticoagulant protein, TFPI.

2.1. Molecular Target: Tissue Factor Pathway Inhibitor (TFPI)

The specific molecular target of KN-057 is Tissue Factor Pathway Inhibitor (TFPI).[1] TFPI is a multivalent Kunitz-type serine protease inhibitor that plays a critical role in the physiological downregulation of the extrinsic, or tissue factor-initiated, pathway of coagulation.[3] TFPI primarily exists in two major isoforms, TFPIα and TFPIβ, derived from alternative splicing. TFPIα is found in plasma, associated with lipoproteins, and also bound to the endothelium via glycosaminoglycans, while TFPIβ is predominantly a GPI-anchored protein on the surface of endothelial cells.[3] TFPI exerts its anticoagulant effect through sequential inhibition: its second Kunitz domain (K2) binds to and inhibits FXa, and this TFPI/FXa complex then inhibits the TF/FVIIa complex via TFPI's first Kunitz domain (K1).[3] TFPIα, through its C-terminal basic region and interaction with Protein S, can also inhibit early forms of the prothrombinase complex.[3] The precise binding epitope of KN-057 on TFPI is not detailed in the provided sources, but its neutralizing capacity implies interaction with regions critical for TFPI's anticoagulant function.

2.2. Pharmacological Action: How KN-057 Neutralizes TFPI to Restore Hemostasis

Upon subcutaneous administration, KN-057, as a monoclonal antibody, specifically binds to TFPI and neutralizes its inhibitory functions within the coagulation cascade.[2] By blocking TFPI's ability to inhibit FXa and the TF/FVIIa complex, KN-057 effectively "releases the brakes" on the initial phase of coagulation. This disinhibition allows for more robust generation of FXa by the TF/FVIIa pathway, which in turn leads to an amplification of thrombin generation.[5]

Thrombin is a key enzyme that converts fibrinogen to fibrin, forming a stable clot, and also activates platelets and other coagulation factors, further promoting hemostasis. In individuals with hemophilia, the intrinsic pathway of thrombin generation is impaired due to the deficiency of FVIII or FIX. By enhancing the extrinsic pathway through TFPI inhibition, KN-057 aims to compensate for this deficiency and restore adequate thrombin generation, thereby improving clot formation and reducing bleeding episodes.[5] A critical aspect of this pharmacological action is its independence from FVIII or FIX activity, making KN-057 a viable therapeutic strategy for both hemophilia A and B, including the challenging population of patients who have developed inhibitors against factor replacement products.[3] This rebalancing of the coagulation system, by targeting an inhibitor rather than replacing a deficient factor, represents a novel therapeutic paradigm in hemophilia care.

3. Preclinical Development

The preclinical development of TFPI inhibitors has provided a strong scientific basis for their investigation in hemophilia.

3.1. In Vitro Characterization

Specific in vitro biochemical data for KN-057, such as its binding affinity (e.g., K_D) to human TFPI or its IC₅₀ for TFPI functional inhibition in purified systems, are not detailed in the provided research snippets. However, highly relevant ex vivo pharmacodynamic data were generated as part of the Phase 1 clinical trial program. In an ex vivo study using platelet-poor plasma from hemophilia patients (covering hemophilia A with and without inhibitors, and hemophilia B with and without inhibitors), KN-057 demonstrated a concentration-dependent increase in peak thrombin generation and endogenous thrombin potential (ETP). This effect was observed to reach its maximum at a KN-057 concentration of 28 nM.[5] This finding, obtained in the complex biological milieu of human hemophilic plasma, strongly supports the intended procoagulant mechanism of action of KN-057 and its potential to correct the thrombin generation deficit characteristic of hemophilia.

3.2. In Vivo Animal Models of Hemophilia

The general concept of TFPI inhibition for hemophilia treatment has been validated in various animal models. Studies in hemophilic mice, dogs, rabbits, and monkeys have shown that inhibiting TFPI activity can mitigate bleeding phenotypes.[3] These foundational studies established TFPI as a viable therapeutic target for hemophilia. However, the provided research snippets do not contain specific in vivo preclinical efficacy data for KN-057 itself, such as results from bleeding models in hemophilic animals treated with KN-057 or detailed in vivo coagulation parameter changes. The progression of KN-057 to human clinical trials suggests that such supportive preclinical efficacy data were likely generated and reviewed by regulatory authorities.

3.3. Safety Pharmacology and Toxicology

Detailed preclinical safety pharmacology and toxicology reports specific to KN-057 are not available within the provided snippets.[32] Standard preclinical safety evaluations, including Good Laboratory Practice (GLP) toxicology studies, are mandatory before initiating human trials and would have assessed potential on-target (e.g., prothrombotic risk) and off-target toxicities. The advancement of KN-057 into Phase 3 clinical trials implies that an acceptable preclinical safety profile was demonstrated to regulatory bodies such as the NMPA in China and the FDA in the context of its Orphan Drug Designation review.

4. Clinical Development Program in Hemophilia

KN-057 is undergoing a comprehensive clinical development program aimed at establishing its efficacy and safety as a prophylactic treatment for hemophilia A and B, including patients with inhibitors.

4.1. Overview of Clinical Strategy and Trial Phases

The clinical strategy for KN-057 focuses on its use as a prophylactic agent, administered subcutaneously, with the potential for once-weekly dosing. The program has systematically progressed through Phase 1 studies in healthy volunteers, Phase 2 studies in hemophilia patients to evaluate dose, safety, PK, and PD, and is now in pivotal Phase 3 trials.[1] Key trials are summarized in Table 1.

Table 1: Overview of KN-057 Clinical Trials

Trial ID (NCT/CTR)	Phase	Status	Indication(s)	Key Objectives	Patient Population (Age, Severity, Inhibitor Status)	Regions/Countries
CTR20220429 / CTR20201606	Phase 1	Completed	Healthy Volunteers	Safety, PK, ex vivo PD	Healthy Males	China
KN057-A-201 (NCT05421429)	Phase 2	Completed	Hemophilia A or B, with/without inhibitors	Safety, Tolerability, PK, PD	Adults (18-70 yrs), Mod-Severe (FVIII/FIX ≤2%)	China
KN057-A-202 (NCT06747416)	Phase 2	Not yet recruiting (Planned Feb 2025)	Severe HA or Mod-Severe HB, with/without inhibitors	Safety, Tolerability, Efficacy, PK, PD	Males	China
KN057-A-301 (NCT06312475)	Phase 3	Recruiting	Hemophilia A or B with inhibitors	Efficacy, Safety	Adolescents & Adults (12-70 yrs), ≥6 bleeds/26 wks	China
KN057-A-302 (NCT06569108)	Phase 3	Recruiting	Hemophilia A or B without inhibitors	Efficacy, Safety	Adolescents & Adults (≥12 yrs)	China
CTR20234255	Phase 3	Recruiting	Hemophilia A or B without inhibitors	Efficacy, Safety	Not specified in detail	China

Sources:.[1]

This table provides a structured overview of the KN-057 clinical program, consolidating key trial details. It illustrates the progression from early-phase studies in healthy volunteers to late-stage pivotal trials in diverse hemophilia patient populations, including those with and without inhibitors, and across different age groups. The geographical focus appears to be primarily China for the currently active trials.

4.2. Phase 1 Studies

4.2.1. Study in Healthy Volunteers (CTR20220429 / CTR20201606; Results presented by Dr. Feng Xue, ISTH 2024, Abstract PB0242)

This initial human study was a single-dose escalation, randomized, double-blind, placebo-controlled Phase 1 clinical trial conducted in China with healthy male volunteers.[5] Participants received KN-057 at doses ranging from 0.05 mg/kg to 2.5 mg/kg via subcutaneous administration.

Safety: The study reported an overall good safety profile for KN-057 in healthy subjects. Critically, no thromboembolic events were observed, which is a key safety consideration for a procoagulant therapy.[5]

Pharmacokinetics (PK): In the 1.0 mg/kg and 2.5 mg/kg dose groups, the maximum plasma concentration (Cmax) was reached at approximately 48 hours post-administration. The elimination half-life (t_1/2) was determined to be approximately one week. KN-057 demonstrated typical non-linear metabolic characteristics.[5] This pharmacokinetic profile, particularly the half-life, supports the potential for a convenient once-weekly subcutaneous dosing regimen.

Pharmacodynamics (PD) (ex vivo): An ex vivo pharmacodynamic component of the study utilized platelet-poor plasma samples from patients with various types of hemophilia (10 with hemophilia A [HA], 6 with hemophilia B, 6 with hemophilia A with inhibitors [HAW], and 3 with hemophilia B with inhibitors). The addition of KN-057 to these plasma samples resulted in a concentration-dependent increase in peak thrombin generation and endogenous thrombin potential (ETP). This effect reached its maximum at a KN-057 concentration of 28nM. Importantly, the trends and effective concentration ranges of KN-057 were consistent across plasma samples from all tested hemophilia types.[5]

Study Conclusions: The investigators concluded that KN-057 exhibits a favorable safety profile and a half-life suitable for convenient once-a-week subcutaneous administration, which could improve treatment compliance. The ability of KN-057 to increase ex vivo thrombin generation across all hemophilia types assessed indicates its potential as a prophylactic agent for a broad range of hemophilia patients.[5] This early human data provided a strong basis for progressing KN-057 into patient trials, demonstrating both acceptable safety in healthy individuals and mechanistic activity in the target patient biological matrix.

4.3. Phase 2 Clinical Program

Following the encouraging Phase 1 results, KN-057 advanced into Phase 2 clinical trials to evaluate its safety, tolerability, PK, PD, and preliminary efficacy in patients with hemophilia.

4.3.1. KN057-A-201 (NCT05421429): Multiple Subcutaneous Doses in Hemophilia A or B, with or without Inhibitors

This Phase 2 study was an open-label, multicenter, dose-escalation trial designed to evaluate multiple subcutaneous doses of KN-057.1

Status: The trial is reported as completed, with a primary completion date of January 17, 2024, and an estimated study completion date of December 30, 2024.1

Enrollment: The study enrolled 24 adult male participants, aged 18 to 70 years, with moderately severe to severe hemophilia A or B (defined as FVIII or FIX activity ≤2%). This included 18 patients without inhibitors and 6 patients with inhibitors.12

Intervention: Participants received multiple subcutaneous doses of KN-057, with different dose cohorts (Dose I, Dose II, Dose III) being evaluated, though specific dosages for these cohorts are not detailed in the available snippets.12

Primary Outcome Measures: The primary objectives focused on safety and tolerability, including the number of participants with adverse events (AEs), abnormal laboratory findings (particularly coagulation parameters such as PT, INR, APTT, TT, fibrinogen, D-dimer, FDP, AT-III), clinically significant changes in vital signs and electrocardiograms (ECGs), and the incidence of injection site reactions. These were assessed from Day 1 up to Day 85.12

Secondary Outcome Measures: Secondary endpoints included pharmacokinetic parameters (Cmax, Tmax, and AUClast of KN057 from Day 1 up to Day 8; Cmax,ss from Day 36 up to Day 43) and pharmacodynamic markers (levels of Total TFPI and Free TFPI, assessed from the start of KN-057 treatment up to 4 weeks after the last dose).12

Results: Specific efficacy data or detailed safety results from this completed Phase 2 study (KN057-A-201) are not provided in the currently available research snippets. The trial's progression to Phase 3 development suggests that the outcomes were sufficiently positive regarding safety and showed adequate PK/PD target engagement and/or preliminary efficacy signals to warrant further investigation. Ozmosi, a pharmaceutical intelligence platform, assigned this trial a 50% Probability of Success, a typical industry estimation for assets transitioning from Phase 2 to Phase 3.1

4.3.2. NCT06747416 (KN057-A-202): Multiple Subcutaneous Injections in Severe HA or Moderate-to-Severe HB with/without Inhibitors

This is a planned Phase 2 multicenter, open-label study intended to further evaluate the safety, tolerability, efficacy, PK, and PD profile of multiple subcutaneous injections of KN-057 in male patients with severe hemophilia A or moderate-to-severe hemophilia B, with or without inhibitors.8

Status: As of early 2025, this trial was listed as "Not yet recruiting," with a planned start date of February 2025.25 This study likely aims to gather additional data, possibly in specific patient subgroups or to refine dosing regimens, in conjunction with the ongoing Phase 3 program.

4.4. Phase 3 Clinical Program

The KN-057 development program has advanced into pivotal Phase 3 trials, primarily focused on the Chinese patient population, targeting both inhibitor and non-inhibitor segments of hemophilia A and B.

4.4.1. KN057-A-301 (NCT06312475): Prophylaxis in Hemophilia A or B with Inhibitors

This is a randomized, open-label Phase 3 study evaluating the efficacy and safety of KN-057 injection for prophylaxis in patients with hemophilia A or B who have developed inhibitors.1

Status: Actively recruiting, with an actual start date of January 9, 2024.1

Enrollment: The study aims to enroll an estimated 51 male participants, aged 12 to 70 years, with a bodyweight ≥25 kg and BMI <28 kg/m².7

Design: Participants are randomized in a 2:1 ratio to either KN-057 prophylaxis (Arm 1) or No Prophylaxis (Arm 2). Arm 1 receives KN-057 prophylaxis for 52 weeks. Arm 2 initially receives on-demand treatment for 26 weeks and then switches to KN-057 prophylaxis for an additional 26 weeks. The total trial duration for participants is approximately 59 weeks, including screening, treatment, and follow-up.7

Key Inclusion Criteria: Patients must have a documented history of FVIII or FIX inhibitors, either with a high titer (≥5 Bethesda Units/mL) at screening or a low titer (0.6 BU/mL to <5 BU/mL) at screening coupled with a history requiring bypassing agents for treatment. Additionally, participants must have experienced ≥6 treated bleeding episodes within the 26 weeks prior to screening and be willing to washout prior hemophilia treatments as per protocol (e.g., ≥48 hours for rFVIIa, ≥72 hours for FVIII/PCC, ≥96 hours for FIX).7

Key Exclusion Criteria: Include serious or poorly controlled chronic diseases, a history of thromboembolic disease or current high-risk factors for thrombosis (such as coronary atherosclerotic disease, ischemic disease of important organs, vascular occlusive disease, or autoimmune diseases with high thrombotic risk), ongoing or planned immune tolerance induction therapy, previous ineffectiveness of rFVIIa necessitating PCC treatment for bleeds, prior use of TFPI antibody drugs, or major surgery within 3 months before screening or planned during the study.7

Primary Outcome: While not explicitly stated for this specific trial in snippet 7, the common primary endpoint for hemophilia prophylaxis trials, such as ABR, is anticipated.

This trial targets a patient population with significant unmet medical needs. The use of a crossover design in the control arm ensures that all participants have the opportunity to receive KN-057, which can be beneficial for recruitment and ethical considerations in studies involving severe conditions with limited treatment options.

4.4.2. KN057-A-302 (NCT06569108): Prophylaxis in Hemophilia A or B without Inhibitors

This is a randomized, open-label Phase 3 study assessing the efficacy and safety of KN-057 injection for prophylaxis in patients with hemophilia A or B who do not have inhibitors.1

Status: Actively recruiting, with an actual start date of April 1, 2024.1

Enrollment: The study aims to enroll an estimated 111 participants.8

Design: The study includes participants who were receiving on-demand treatment prior to screening; these are randomized 2:1 into an Experimental group (KN-057 weekly SC for 52 weeks) or a Control group (on-demand treatment for 26 weeks, followed by a switch to KN-057 weekly SC for 26 weeks). A third group, the Prophylaxis group, includes participants who were on a prior prophylactic regimen; these participants will receive KN-057 weekly SC for 52 weeks.36

Primary Outcome Measure (Part A - On-demand to KN-057): Annualized bleeding rate (ABR) based on treated spontaneous and traumatic bleeding episodes, comparing the Experimental group (KN-057) to the Control group (on-demand) during the first 26 weeks.36

Secondary Outcome Measures: Include ABR during Weeks 27-52, proportion of participants with untreated bleeding episodes, change from baseline in Hemophilia Joint Health Score (HJHS), change in quality of life (EQ-5D-5L), overall safety, and PK/PD parameters.36

This trial is designed to establish KN-057 as a prophylactic option for the broader non-inhibitor hemophilia population, using a direct comparison against on-demand treatment to demonstrate prophylactic efficacy. The inclusion of a cohort already on prophylaxis transitioning to KN-057 will also provide valuable comparative data.

4.4.3. CTR20234255 (China): Prophylaxis in Hemophilia A and B Without Inhibitors

This Phase 3 trial, registered in China, is also actively recruiting. Its translated title is: "A randomized, open-label study to evaluate the efficacy and safety of KN057 injection for prophylactic treatment in patients with hemophilia A and hemophilia B without inhibitors".[29] This study appears to be the Chinese registration equivalent or a closely related study to NCT06569108, focusing on the non-inhibitor population within China.

4.5. Summary of Clinical Efficacy (Anticipated based on trial designs)

The primary efficacy endpoint for the ongoing Phase 3 trials is generally the Annualized Bleeding Rate (ABR), a standard measure for assessing the effectiveness of prophylactic treatments in hemophilia.[36] Secondary endpoints are designed to capture broader clinical benefits, including joint health status (using the Hemophilia Joint Health Score - HJHS), patient-reported quality of life (using the EQ-5D-5L instrument), and the proportion of patients achieving zero bleeds.[36] Specific efficacy results from these pivotal Phase 3 trials are not yet available as the studies are ongoing. Similarly, detailed efficacy outcomes from the completed Phase 2 trial (KN057-A-201) have not been disclosed in the provided materials.

4.6. Summary of Clinical Safety and Tolerability

Data from the Phase 1 study in healthy volunteers indicated that KN-057 has an overall good safety profile, with no thromboembolic events reported.[5] This is a particularly important early finding for a therapy designed to enhance coagulation. The ongoing Phase 2 and Phase 3 trials are comprehensively monitoring safety, including the incidence of adverse events, laboratory abnormalities (with a focus on coagulation parameters and D-dimer levels), ECG changes, and injection site reactions.[12] The continued absence of significant thrombotic signals in larger patient populations will be crucial for the overall risk-benefit assessment of KN-057.

5. Pharmacokinetics and Pharmacodynamics (Human Data)

Human pharmacokinetic (PK) and pharmacodynamic (PD) data for KN-057 are emerging from its clinical development program.

5.1. Absorption, Distribution, Metabolism, and Excretion (ADME) Profile

Route of Administration: KN-057 is administered via subcutaneous (SC) injection in all clinical trials described.[1]

Pharmacokinetics in Healthy Volunteers (Phase 1, ISTH 2024 abstract PB0242):

A single-dose escalation study in healthy male volunteers (doses from 0.05 to 2.5 mg/kg SC) provided initial human PK data 5:

• Absorption (Tmax): For the 1.0 mg/kg and 2.5 mg/kg dose levels, the time to reach maximum plasma concentration (Tmax) was approximately 48 hours post-administration.
• Elimination Half-life (t_1/2): The elimination half-life was observed to be approximately one week.
• Metabolic Characteristics: KN-057 exhibited typical non-linear metabolic characteristics. This implies that processes such as target-mediated drug disposition (TMDD) might be involved, where binding to TFPI influences its clearance, or that saturable clearance mechanisms are at play.

Pharmacokinetics in Patients (Phase 2, NCT05421429):

The Phase 2 study (KN057-A-201) included PK assessments as secondary outcome measures, specifically Cmax, Tmax, and AUClast of KN057 (evaluated from Day 1 up to Day 8 after initial dosing) and Cmax at steady-state (Cmax,ss) (evaluated from Day 36 up to Day 43, suggesting weekly dosing).12 Specific PK data from this patient trial are not yet available in the provided snippets.

Table 2: Summary of Key Human Pharmacokinetic Parameters of KN-057 (from Phase 1 in Healthy Volunteers)

Parameter	Value/Observation	Source
Dose Range Studied	0.05-2.5 mg/kg SC	5
Tmax (at 1.0 & 2.5 mg/kg)	~48 hours	5
Half-life (t<sub>1/2</sub>)	Approximately 1 week	5
Metabolic Characteristics	Non-linear	5

This table summarizes the earliest available human PK data, which is fundamental for understanding the drug's behavior in the body and supporting dose regimen selection.

The observed half-life of approximately one week is a significant finding, as it strongly supports the feasibility of a convenient once-weekly subcutaneous dosing regimen. This offers a potential major advantage over therapies requiring more frequent administration. The non-linear pharmacokinetic behavior indicates that changes in dose may not result in proportional changes in drug exposure, a factor that requires careful modeling and consideration for dose selection and optimization in later-phase trials to ensure consistent and efficacious exposures.

5.2. Pharmacodynamic Effects

Ex vivo in Hemophilia Patient Plasma (Phase 1 data, ISTH 2024 abstract PB0242):

The Phase 1 program included an important ex vivo pharmacodynamic component 5:

• KN-057 demonstrated a concentration-dependent increase in peak thrombin generation and endogenous thrombin potential (ETP) when added to platelet-poor plasma samples obtained from patients with hemophilia A (with and without inhibitors) and hemophilia B (with and without inhibitors).
• The maximum effect on thrombin generation parameters was observed at a KN-057 concentration of 28 nM.
• Crucially, the trends in thrombin generation enhancement and the effective concentration ranges for KN-057 were consistent across all types of hemophilia plasma tested.

In Patients (Phase 2, NCT05421429):

Pharmacodynamic assessments in the Phase 2 trial included the measurement of levels of Total TFPI and Free TFPI in patients.36 These measurements would directly confirm target engagement by KN-057 and help correlate drug exposure with the extent of TFPI neutralization. Specific data from these patient PD assessments are not yet available in the provided snippets.

Table 3: Summary of Key Pharmacodynamic Effects of KN-057

PD Marker	Effect Observed / To Be Measured	Concentration/Dose for Effect	Patient Population / Matrix	Source
Peak Thrombin	Increased	Peak effect at 28nM (ex vivo)	Hemophilia A & B (with/without inhibitors) patient plasma	5
Endogenous Thrombin Potential (ETP)	Increased	Peak effect at 28nM (ex vivo)	Hemophilia A & B (with/without inhibitors) patient plasma	5
Total TFPI Levels	To be measured in patients	Not Applicable	Hemophilia A or B patients (Phase 2)	36
Free TFPI Levels	To be measured in patients	Not Applicable	Hemophilia A or B patients (Phase 2)	36

This table demonstrates KN-057's biological activity, linking its mechanism (TFPI inhibition) to measurable effects on coagulation (thrombin generation) and direct target engagement (TFPI levels).

The consistent ex vivo pharmacodynamic effects observed across different types of hemophilia plasma, including those from patients with inhibitors, provide strong support for the broad therapeutic potential of KN-057. This directly demonstrates that KN-057 can enhance the fundamental deficient process (thrombin generation) in the relevant biological context. The planned measurement of free and total TFPI levels in patient trials will be critical for confirming in vivo target engagement and understanding the exposure-response relationship.

6. Regulatory Status and Intellectual Property

KN-057 has achieved notable regulatory milestones and is protected by intellectual property rights held by its developer.

6.1. United States (Food and Drug Administration - FDA)

KN-057, under the name Armocibart, received Orphan Drug Designation (ODD) from the U.S. FDA for the treatment of Hemophilia A in March 2024 [[2] (cfgridkey=994023)]. This designation is granted to drugs intended for rare diseases or conditions and provides significant development incentives, including potential market exclusivity upon approval, tax credits for clinical research, and waiver of certain FDA fees. The granting of ODD signifies FDA's recognition of hemophilia A as a serious condition and of KN-057's potential to provide a clinical benefit.

6.2. China (National Medical Products Administration - NMPA)

The Investigational New Drug (IND) application for KN-057 (CXSL1900141) was approved by the NMPA on December 21, 2019.[2] Following this approval, multiple clinical trials, including the ongoing Phase 3 studies (KN057-A-301/NCT06312475, KN057-A-302/NCT06569108, and CTR20234255), are actively recruiting patients in China.[1] There is no mention in the provided snippets of KN-057 having received special review pathways such as Breakthrough Therapy Designation or specific orphan drug status from the NMPA, although such designations may exist or be pursued. The active late-stage clinical development underscores a clear regulatory pathway being followed in this key market.

6.3. Europe (European Medicines Agency - EMA) and Other Regions

The provided research snippets do not contain specific information regarding the regulatory status or filings for KN-057 with the European Medicines Agency (EMA) or other regulatory authorities outside of the US and China.

6.4. Patent Landscape

KN-057 is described as a monoclonal antibody independently developed by Suzhou Alphamab Biotechnology Co., Ltd., with the company holding independent intellectual property rights.2

Several patent documents related to anti-TFPI antibodies, potentially covering KN-057 or similar molecules, have been identified:

• U.S. Patent Application Publication US-20180334509-A1 (published November 22, 2018) discloses isolated monoclonal antibodies that bind human TFPI and methods of treating coagulation deficiencies.[39]
• U.S. Patent Application Publication US-20180194857 (published July 12, 2018) also pertains to isolated monoclonal antibodies binding specific epitopes of human TFPI and their therapeutic use.[40]
• European Patent EP4070817A1, with Suzhou Alphamab Biotechnology listed, also relates to TFPI antibodies.[41] While these snippets do not definitively link these specific patent documents directly to KN-057 by name, their subject matter (anti-TFPI monoclonal antibodies for coagulation disorders) and applicant/assignee information strongly suggest they form part of the intellectual property portfolio protecting KN-057 or the underlying technology. A robust patent position is crucial for protecting the innovation and securing future commercialization.

7. Discussion, Conclusion, and Future Outlook

7.1. Synthesis of Key Findings: Efficacy, Safety, and PK/PD Profile

KN-057 (Armocibart) is an anti-TFPI monoclonal antibody administered subcutaneously, currently in late-stage clinical development for hemophilia A and B, including patients with inhibitors. Phase 1 studies in healthy volunteers demonstrated a good safety profile, notably with no thromboembolic events, and a pharmacokinetic profile supportive of a once-weekly dosing regimen (t_1/2 ~1 week).[5] Ex vivo pharmacodynamic studies using plasma from hemophilia patients showed that KN-057 effectively enhances thrombin generation in a concentration-dependent manner, consistently across different hemophilia types and inhibitor statuses.[5] A Phase 2 study (KN057-A-201) in hemophilia patients has been completed, and while detailed results are not available in the provided sources, its completion has paved the way for ongoing Phase 3 pivotal trials.[1] These Phase 3 studies are actively recruiting in China, evaluating the efficacy (primarily ABR) and safety of KN-057 as a prophylactic treatment.[7]

7.2. Potential Advantages and Clinical Significance of KN-057

KN-057 offers several potential advantages over existing hemophilia therapies:

• Broad Applicability: Its mechanism of inhibiting TFPI is independent of FVIII or FIX activity. This implies efficacy for both hemophilia A and B, and crucially, for patients who have developed inhibitors to factor replacement therapy—a group with high unmet medical need.[3] This could significantly simplify treatment paradigms.
• Improved Convenience and Compliance: The subcutaneous route of administration and the potential for a once-weekly dosing schedule [5] offer a substantial improvement in convenience and quality of life compared to the frequent intravenous infusions required for many current factor replacement therapies.[13] This is likely to lead to better adherence to prophylactic regimens, potentially resulting in improved long-term outcomes, such as reduced joint damage.
• Novel Mechanism of Action: By "rebalancing" the coagulation system through the inhibition of a natural anticoagulant (TFPI), KN-057 may offer a more physiological approach to hemostasis compared to the supraphysiological levels often achieved with factor replacement. This could potentially lead to a more stable hemostatic effect and possibly a different safety profile, particularly concerning the development of new inhibitors (though this needs long-term evaluation).

7.3. Comparative Assessment

The provided information does not contain sufficient data to perform a direct comparative assessment of KN-057 against other TFPI inhibitors currently in development [13] or other emerging non-factor therapies for hemophilia. Such an assessment would require access to more detailed clinical trial results, including head-to-head studies or robust comparative meta-analyses, which are beyond the scope of the current material.

7.4. Unanswered Questions and Areas for Future Research

Several key questions remain to be addressed as the clinical development of KN-057 progresses:

• Detailed Phase 2 Efficacy and Safety: The specific efficacy outcomes (e.g., ABR reduction, joint health improvement) and the full safety profile from the completed Phase 2 trial (KN057-A-201) are critical for a comprehensive understanding of its risk-benefit profile in patients.
• Phase 3 Outcomes: The results from the ongoing pivotal Phase 3 trials will be paramount in determining the definitive efficacy and long-term safety of KN-057 in larger, more diverse patient populations, including both inhibitor and non-inhibitor patients.
• Immunogenicity: As with all protein-based therapeutics, the potential for immunogenicity (development of anti-drug antibodies) against KN-057 needs to be thoroughly evaluated, as this could impact its efficacy and safety over long-term use.
• Long-Term Safety: Particularly concerning thrombotic risk, although early data is reassuring [5], long-term surveillance in larger patient populations is essential for a procoagulant therapy.
• Positioning in the Evolving Treatment Landscape: The role of KN-057 relative to other novel non-factor therapies and emerging gene therapies for hemophilia will need to be defined based on comparative efficacy, safety, durability of effect, patient preference, and cost-effectiveness.
• Global Development Strategy: While development is active in China and ODD has been granted in the US, the broader global development and regulatory strategy, particularly in Europe, remains to be fully elucidated.

7.5. Market Potential and Concluding Remarks

The global hemophilia market represents a significant therapeutic area with ongoing unmet medical needs, especially for patients with inhibitors and those seeking less burdensome treatment regimens. If the Phase 3 trials confirm the promising early signals of efficacy, safety, and convenience, KN-057 (Armocibart) has the potential to become a valuable therapeutic option. Its broad applicability across hemophilia types and inhibitor statuses, combined with a patient-friendly subcutaneous once-weekly dosing schedule, could allow it to capture a substantial share of the prophylactic treatment market. The strategic partnership for Greater China [2] and the U.S. FDA Orphan Drug Designation [11] suggest a focused initial market entry strategy with potential for wider global reach.

In conclusion, KN-057 (Armocibart) is a rationally designed anti-TFPI monoclonal antibody that represents a promising advancement in the treatment of hemophilia. Its novel mechanism of action, potential for broad patient applicability, and convenient administration route address key limitations of current therapies. The progression to late-stage clinical trials, supported by positive early-phase safety and pharmacodynamic data, positions KN-057 as a significant candidate in the evolving landscape of hemophilia care. The forthcoming results from the pivotal Phase 3 studies will be crucial in defining its ultimate clinical role and therapeutic value.

8. References

1 Ozmosi. KN-057 Drug Profile. Ozmosi. Last Update: 2024-12-30.

24 Synapse. What is KN-057 used for? Patsnap Synapse.

12 ngram.com. NCT05421429: An Open, Multicenter, Dose Escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Multiple Subcutaneous (SC) Doses of KN057 in Subjects with Hemophilia a or B, with or Without Inhibitors.

35 Veeva Clinical Trials. KN057 Multiple Dose Study in Moderately Severe to Severe Hemophilia. CTV.veeva.com.

3 Mast AE. TFPIα and TFPIβ in Coagulation and Vascular Biology. Arterioscler Thromb Vasc Biol. 2016.

4 Wood JP, et al. The role of tissue factor pathway inhibitor in the control of coagulation. Blood. 2014.

25 AdisInsight. KN 057. Springer Nature. Last Information Update: 31 Dec 2024.

1 Synapse. KN-057 - Drug Targets, Indications, Patents. Patsnap Synapse. Last update: 2024-12-30.

36 connect.careboxhealth.com. Trial Listing for NCT06569108: Efficacy and Safety of KN057 Prophylaxis in Patients With Haemophilia A or B Without Inhibitors.

28 Synapse. Suzhou Alphamab Co., Ltd. - Drug pipelines, Patents, Clinical trials. Patsnap Synapse.

44 Alphamab Oncology. Press Release: Alphamab Oncology Entered a Partnership Agreement with Raygene Pharmaceutical. 2021-09-28.

13 Kumar R, et al. Revolutionizing Treatment Strategies through Inhibition of Tissue Factor Pathway Inhibitor: A Promising Therapeutic Approach for Hemophilia Management. J Assoc Physicians India. 2025 Apr.

1 Ozmosi. KN-057 Drug Profile.1

7 ngram.com. NCT06312475: A Randomized, Open-label Study to Evaluate the Efficacy and Safety of KN057 Injection Prophylaxis in Patients With Hemophilia A or B With Inhibitors.

3 Mast AE..3

39 Patent US-20180334509-A1. Isolated monoclonal antibodies that bind human tissue factor pathway inhibitor (TFPI) and methods of use. Patent Buddy.

40 Patent US-20180194857-A1. Isolated monoclonal antibodies that bind to specific epitopes of human tissue factor pathway inhibitor (TFPI) and methods of use. Patent Buddy.

5 Xue F, et al. A phase I trial evaluating safety and pharmacokinetics in human and an ex vivo pharmacodynamics study in hemophilia patients of KN057, the first anti–TFPI monoclonal antibody in China. ISTH 2024 Congress. Abstract PB0242. 2024 Jun 23.

45 Alphamab Oncology. Alphamab Oncology Presented Preclinical Data on Two Novel Bispecific ADCs at the 2025 AACR Annual Meeting. PR Newswire. 2025-04-30.

30 Alphamab Oncology. Pipeline Overview. Alphamab Oncology Official Website.

31 Alphamab Oncology. JSKN003. Alphamab Oncology Official Website.

46 Alphamab Oncology. Alphamab Oncology Collaborated with ArriVent in Relation to the Research, Development and Commercialization of ADC Products. PR Newswire.

28 Synapse. Armocibart - Drug Targets, Indications, Patents. Patsnap Synapse.

2 The Antibody Society. KN057. YAbS Database. Status check date: 2024-03-29.

37 Synapse. Hemophilia A - Drugs, Targets, Patents. Patsnap Synapse. (Mentions NCT06747416).

6 ISTH 2024 Official Platform. PB0242 - A phase I trial evaluating safety and pharmacokinetics in human and an ex vivo pharmacodynamics study in hemophilia patients of KN057, the first anti–TFPI monoclonal antibody in China. Feng Xue. 2024..5

26 The Antibody Society. KN057 (details). YAbS Database..2

47 Alphamab Oncology..45

48 Alphamab Oncology..46

13 Kumar R, et al..13

32 CStone Pharmaceuticals. CStone Announces NMPA Approval of Sugemalimab for R/R ENKTL. PR Newswire. 2023-10-31. (Used for general regulatory context, not KN-057 specific).

38 The Antibody Society..2

9 The Antibody Society..2

27 Ozmosi..1

32 Alphamab Oncology. Alphamab Oncology Reports Full Year 2024 Financial Results and Business Highlights. PR Newswire. 2025-03-26.

33 Alphamab. Pipeline. Alphamab Official Website (alphamab.com).

38 Synapse..28

41 The Antibody Society. (Mentions EP4070817A1).

10 The Antibody Society..2

32 Alphamab Oncology..32

13 JAPI..13

29 Synapse..28

1 Ozmosi..1

8 ngram.com. Drug Profile: Armocibart.

42 The Antibody Society..41

9 The Antibody Society..2

28 Synapse. (Content related to other Alphamab products).

10 The Antibody Society..2

38 The Antibody Society..2

25 AdisInsight. KN 057. Springer Nature. Last Information Update: 31 Dec 2024. (Provides trial IDs NCT06569108, NCT06312475, NCT06747416).

11 FDA. Orphan Drug Product Designation Database. Search for Armocibart (KN-057). cfgridkey=994023. Designation Date: March 2024.

43 Espacenet. Patent EP4070817A1. (Website inaccessible during synthesis).

33 Alphamab. Products. Alphamab Official Website (alphamab.com)..33

49 Alphamab. Products Index. Alphamab Official Website (alphamab.com)..33

Note: Some snippets provided were duplicates or offered very general information not specific to KN-057's detailed profile and were thus consolidated or used for general context. Snippets related to KEYNOTE-057 (pembrolizumab) were excluded as per the clarification.

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