KN057 Multiple Dose Study in Moderately Severe to Severe Hemophilia

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

This study is designed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics and efficacy of multiple subcutaneous doses of KN057 in subjects with hemophilia A or B, with or without inhibitors to Factor VIII (FVIII) or Factor IX (FIX). 24 adult participants 18 to 70 years of age with moderately severe to severe hemophilia A or hemophilia B (defined as FVIII or FIX activity ≤2%, respectively) with or without inhibitors (including 18 HA/HB patients without inhibitors and 6 HA/HB patients with inhibitors) are expected to be enrolled in this study during which they will receive prophylaxis treatment (defined as treatment by SC injection once weekly of KN057).

Study Overview

• Status: Recruiting
• Conditions: Hemophilia
• Intervention / Treatment: Biological: KN057 doseⅠ; Biological: KN057 dose Ⅱ; Biological: KN057 dose Ⅲ

• Study Type: Interventional
• Enrollment (Estimated): 24
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Yanrong Dong, Master; Phone Number: +86 18914005458; Email: yanrongdong@alphamab.com

Study Locations

• China
  • Tianjin
    • Tianjin, Tianjin, China, 300020
      • Recruiting
      • Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences
      • Contact: Renchi Yang, Doctor
    • Tianjin, Tianjin, China, 300020
      • Recruiting
      • stitute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences
      • Contact: Renchi Yang, Doctor

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Male, 18-70 years old (including threshold), weight≥40kg;
2. Moderately severe to severe hemophilia A or B (Factor VIII or Factor IX activity ≤2%)

3. Participants who are enrolled into the Non-Inhibitor Cohort must meet the following criteria:

   ①negtive results of of inhibitors to Factor VIII (FVIII) or Factor IX (FIX) in screening period.

   ②with ≥6 acute bleeding episodes (spontaneous or traumatic, not including episodes of bleeding during surgery) that required treatment within 6 months before screening and willing to continue to receive on-demand treatment during the study.

   ③using coagulation factor replacement therapy for more than 50 exposure days before screening.

4. Participants who are enrolled into the Inhibitor Cohort must meet the following criteria:

   ①positive results of inhibitors to Factor VIII (FVIII) or Factor IX (FIX) in screening period.

   ②with ≥6 acute bleeding episodes (spontaneous or traumatic, not including episodes of bleeding during surgery) that required treatment within 6 months before screening and willing to continue to receive on-demand treatment during the study.

5. Be willing to undergo a washout period of the original treatment regimen before the administration of KN057: at least 48 hours for recombinant activated coagulation factor Ⅶ (rFⅦa); at least 72 hours for FⅧ and prothrombin complex (PCC); at least 96 hours for FⅨ; For other drugs or investigational products with a long half-life, such as Emicizumab, at least five half-lives should have passed prior to dosing.
6. Be willing to comply with the relevant management regulations of the clinical trial unit, and follow study procedures.

Exclusion Criteria:

1. Patients with serious or poorly controlled chronic diseases or obvious systemic diseases, such as cardiovascular system, respiratory system, endocrine and metabolic system, urinary system, digestive system, autoimmune diseases, nervous system diseases or psychiatric diseases, bacterial or viral infections, etc.; past or current lipid-lowering treatment for hypertriglyceridemia.
2. Inherited or acquired bleeding disorder other than hemophilia A or B.
3. Have symptoms or signs related to thromboembolic disease or are receiving thrombolytic/anti-thrombolytic therapy; A history of coronary atherosclerotic diseases, arterial or venous thrombosis, and ischemic diseases of important organs.
4. Conditions that may increase risk of thrombosis: including reduced activity of antithrombin III, protein S or protein C;
5. Must use PCC to treat acute bleeding episodes, and can't be treated with rFVIIa.
6. Ongoing or planned use of immune tolerance induction.
7. Regular use of immunomodulatory therapy, such as regular infusion of immunoglobulin or regular use of hormones.
8. Allergy situation: Allergic to test drugs/similar drugs or excipients; With a history of multiple allergies (two or more); A history of specific reactions, such as sensitivity to heparin or heparin induced thrombocytopenia.
9. Abnormal hematologic parameters: Platelet count≤100×10^9/L; Hemoglobin < 100g/L; Fibrinogen level < LLN; Prothrombin time > 1.5 times ULN;
10. Abnormal renal or hepatic function: Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) > 3 times ULN; Lactate dehydrogenase (LDH) > 1.5 times ULN; Total bilirubin (TB) > 1.5 times ULN; Serum creatinine (Cr) and triglyceride > ULN; Albumin < 0.8 times LLN;
11. Chronic active hepatitis B/C (HBV-DNA or HCV-RNA quantitative test indicates viral activity); Human immunodeficiency virus (HIV) antibody positive; Syphilis antibody positive; Previous antiviral treatment within 1 month, or a plan for antiviral treatment within 28 weeks of initial administration.
12. Had major surgery, as judged by the investigator, within 3 months prior to the study or have elective surgery planned within 28 weeks of initial administration.
13. Need to use anti-fibrinolytic drugs or drugs affecting platelet function 5 days before administration or 28 weeks after initial administration, including Traditional Chinese medicine/proprietary Chinese medicine, such as aspirin and other non-steroidal anti-inflammatory drugs, Angelica, astragalus, etc., or proprietary Chinese medicine containing the above ingredients.
14. Participated in clinical trials related to coagulation factors within 1 month; Participated in any other drug clinical trials within 3 months.
15. Vaccination within 1 month, or within 28 weeks after initial administration, including inactivated vaccines, live attenuated vaccines, recombinant protein vaccines, recombinant adenovirus vaccines, RNA vaccines, DNA vaccines, etc.;
16. Subjects with fertile partners are not willing to use effective contraception during the study period and for 3 months after the last dosing; Effective contraceptive methods include: vasectomy, adhere to the scientific use of male condoms, etc.
17. Other factors that the investigator considers unacceptable for participation in the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: KN057 (Cohort 1：HA/HB); Injection, once a week	Biological: KN057 doseⅠ; KN057 subcutaneous (SC) injection
Experimental: KN057 (Cohort 2：HA/HB); Injection, once a week	Biological: KN057 dose Ⅱ; KN057 SC injection
Experimental: KN057 (Cohort 3：HA/HB); Injection, once a week	Biological: KN057 dose Ⅱ; KN057 SC injection
Experimental: KN057 (Cohort 4：HAW/HBW); Injection, once a week	Biological: KN057 dose Ⅲ; KN057 SC injection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Frequency and severity of treatment emergent adverse events(TEAEs)	An adverse event (AE) is any untoward medical occurrence in a clinical investigation participant administered a product; the event did not need to have a causal relationship with the treatment. A serious adverse event (SAE) is any untoward medical occurrence at any dose that resulted in death; life threatening; required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; resulted in congenital anomaly/birth defect. AEs included both SAEs and non-serious AEs. TEAEs were AEs occurred following the start of treatment or AEs increasing in severity during treatment.	Day 1 up to Day 85
Withdrawals due to TEAEs	An AE is any untoward medical occurrence in a clinical investigation participant administered a product and the event does not need to have a causal relationship with the treatment. TEAEs are AEs occurred following the start of treatment or AEs increasing in severity during treatment.	Day 1 up to Day 85
Number of Participants With Abnormal Laboratory Findings-Hematology	White blood cells, red blood cells; the count of lymphocyte, neutrophils, monocytes, eosinophils, basophils; the percentage of lymphocyte, neutrophils, monocytes, eosinophils, basophils; hemoglobin, red blood cell pressure, platelet count	Day 1 up to Day 85
Number of Participants With Abnormal Laboratory Findings-Urinalysis	blood, urobilirubin, urobiliogen, ketone body, protein, nitrite, red blood cell (qualitative and/or quantitative), white blood cell (qualitative and/or quantitative), pH, urinary glucose.	Day 1 up to Day 85
Number of Participants With Abnormal Laboratory Findings-Blood biochemistry	Total bilirubin and indirect bilirubin, direct bilirubin, alanine aminotransferase, aspertate aminotransferase, GGTP (gamma glutamyl transpeptidase), alkaline phosphatase, total protein, albumin, globulin, albumin-globulin ratio, urea, creatinine, uric acid, glucose, total cholesterol, triglyceride, low density lipoprotein cholesterol (ldl-c), high-density lipoprotein cholesterol (hdl-c), lactate dehydrogenase, creatine kinase, chlorine, calcium, sodium, potassium, C reactive protein	Day 1 up to Day 85
Number of Participants With Abnormal Laboratory Findings-Coagulation tests	Prothrombin time (PT), International Standardized ratio (INR), Activated partial thrombin time (APTT), thrombin time (TT), fibrinogen (FBG/FIB), D-dimer (D-DI), fibrinogen degradation product (FDP), antithrombin - ⅲ (AT- ⅲ)	Day 1 up to Day 85
Number of Participants With Clinically Significant Changes in Vital Signs Data	Vital signs：blood pressure (systolic blood pressure, diastolic blood pressure), respiration, temperature, pulse；	Day 1 up to Day 85
Number of Participants With Clinically Significant Changes in Electrocardiogram (ECG)	ECG: HR; RR; PR; QRS; QT; QTc	Day 1 up to Day 85
Number of Participants With Clinically Significant Changes in Physical Examination Findings	Physical examination included head, ears, eyes, nose, mouth, skin, heart and lung examinations, lymph nodes, gastrointestinal, musculoskeletal, and neurological systems. Clinical significance was judged by the investigator.	Day 1 up to Day 85
Number of Participants With Injection Site Reactions	Injection site reactions may include, but are not limited to: erythema, sclerosis, ecchymosis, pain, and itching.	Day 1 up to Day 85

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Plasma Concentration (Cmax) of KN057		Day 1 up to Day 8
Time to Reach Maximum Plasma Concentration (Tmax) of KN057		Day 1 up to Day 8
Area Under the Concentration-time Profile From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of KN057		Day 1 up to Day 8
Cmax,ss: Maximum observed KN057 concentration at steady-state		Day 36 up to Day 43
Time to Reach Maximum Plasma Concentration at steady-state (Tmax,ss) of KN057		Day 36 up to Day 43
Area Under the Serum Concentration-time Curve Over the Dosing Interval Tau (AUCtau) of KN057		Day 36 up to Day 43
Apparent Clearance (CL/F) of KN057		Day 36 up to Day 43
Lowest Concentration Observed During the Dosing Interval (Cmin) of KN057		Day 36 up to Day 43
Pharmacodynamics index: Changes of TFPI from baseline;	Tissue factor (TF) pathway inhibitor (TFPI) is an anticoagulant protein that inhibits early phases of the procoagulant response. TFPI: Total TFPI, Free TFPI	Day 1 up to Day 169
Pharmacodynamics index: Changes of Prothrombin fragment 1+2 (PF1+2) from baseline;	Prothrombin fragment 1+2 (F1+2) is the amino terminus fragment of the prothrombin molecule.	Day 1 up to Day 169
Pharmacodynamics index: Thrombin Generation (TGA);	Lag Time; Peak Thrombin; Endogenous Thrombin Potential;	Day 1 up to Day 169
Number of Participants Who Tested Positive for Anti-KN057 Antibody (ADA)	Human plasma ADA samples were analyzed for the detection of anti KN057 antibodies.	Day 1 up to Day 169
Number of Participants Who Tested Positive for Neutralizing Antibody (NAb)	Human plasma NAb samples were analyzed for the presence or absence of NAb to KN057.	Day 1 up to Day 169
Annualized Bleeding Rate	ABR = number of bleeds requiring treatments/ (days on treatment period / 365.25)	Day 1 up to Day 169

Collaborators and Investigators

• Sponsor: Suzhou Alphamab Co., Ltd.
• Investigators: Principal Investigator: Renchi Yang, Doctor, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences; Principal Investigator: Shujie Wang, Doctor, Peking Union Medical College Hospital; Principal Investigator: Hu Zhou, Doctor, Henan Cancer Hospital（The Affiliated Cancer Hospital Of ZhengZhou University); Principal Investigator: Ziqiang Yu, Doctor, The First Affiliated Hospital of Soochow University; Principal Investigator: Changcheng Zheng, Doctor, The First Affiliated Hospital of USTC (Anhui Provincial Hospital); Principal Investigator: Xielan Zhao, Doctor, Xiangya Hospital of Central South University; Principal Investigator: Jing Sun, Doctor, Nanfang Hospital, Southern Medical University

Study record dates

Study Major Dates

• Study Start (Actual): July 7, 2022
• Primary Completion (Actual): February 28, 2024
• Study Completion (Estimated): June 30, 2024

Study Registration Dates

• First Submitted: June 9, 2022
• First Submitted That Met QC Criteria: June 13, 2022
• First Posted (Actual): June 16, 2022

Study Record Updates

• Last Update Posted (Actual): March 12, 2024
• Last Update Submitted That Met QC Criteria: March 8, 2024
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Hematologic Diseases; Blood Coagulation Disorders, Inherited; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Blood Coagulation Disorders; Hemophilia A
• Other Study ID Numbers: KN057-A-201

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No