Clinical trial NCT05421429: KN057 Multiple Dose Study in Moderately Severe to Severe Hemophilia
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Hemophilia
Lead sponsor: Suzhou Alphamab Co., Ltd.
Sponsor class: INDUSTRY
First posted: 2022-06-16
Enrollment: 24
Sex: MALE
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: PREVENTION

Brief summary: 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).


Eligibility criteria: 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.

Primary outcomes:
measure: Frequency and severity of treatment emergent adverse events(TEAEs)
timeFrame: Day 1 up to Day 85
measure: Withdrawals due to TEAEs
timeFrame: Day 1 up to Day 85
measure: Number of Participants With Abnormal Laboratory Findings-Hematology
timeFrame: Day 1 up to Day 85
measure: Number of Participants With Abnormal Laboratory Findings-Urinalysis
timeFrame: Day 1 up to Day 85
measure: Number of Participants With Abnormal Laboratory Findings-Blood biochemistry
timeFrame: Day 1 up to Day 85
measure: Number of Participants With Abnormal Laboratory Findings-Coagulation tests
timeFrame: Day 1 up to Day 85
measure: Number of Participants With Clinically Significant Changes in Vital Signs Data
timeFrame: Day 1 up to Day 85
measure: Number of Participants With Clinically Significant Changes in Electrocardiogram (ECG)
timeFrame: Day 1 up to Day 85
measure: Number of Participants With Clinically Significant Changes in Physical Examination Findings
timeFrame: Day 1 up to Day 85
measure: Number of Participants With Injection Site Reactions
timeFrame: Day 1 up to Day 85
Secondary outcomes:
measure: Maximum Plasma Concentration (Cmax) of KN057
timeFrame: Day 1 up to Day 8
measure: Time to Reach Maximum Plasma Concentration (Tmax) of KN057
timeFrame: Day 1 up to Day 8
measure: Area Under the Concentration-time Profile From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of KN057
timeFrame: Day 1 up to Day 8
measure: Cmax,ss: Maximum observed KN057 concentration at steady-state
timeFrame: Day 36 up to Day 43
measure: Time to Reach Maximum Plasma Concentration at steady-state (Tmax,ss) of KN057
timeFrame: Day 36 up to Day 43
measure: Area Under the Serum Concentration-time Curve Over the Dosing Interval Tau (AUCtau) of KN057
timeFrame: Day 36 up to Day 43
measure: Apparent Clearance (CL/F) of KN057
timeFrame: Day 36 up to Day 43
measure: Lowest Concentration Observed During the Dosing Interval (Cmin) of KN057
timeFrame: Day 36 up to Day 43
measure: Pharmacodynamics index: Changes of TFPI from baseline;
timeFrame: Day 1 up to Day 169
measure: Pharmacodynamics index: Changes of Prothrombin fragment 1+2 (PF1+2) from baseline;
timeFrame: Day 1 up to Day 169
measure: Pharmacodynamics index: Thrombin Generation (TGA);
timeFrame: Day 1 up to Day 169
measure: Number of Participants Who Tested Positive for Anti-KN057 Antibody (ADA)
timeFrame: Day 1 up to Day 169
measure: Number of Participants Who Tested Positive for Neutralizing Antibody (NAb)
timeFrame: Day 1 up to Day 169
measure: Annualized Bleeding Rate
timeFrame: Day 1 up to Day 169
Other outcomes:
Locations:
city: Tianjin
country: China
facility: Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences
state: Tianjin
city: Tianjin
country: China
facility: stitute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences
state: Tianjin
Study officials:
affiliation: Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences
name: Renchi Yang, Doctor
role: PRINCIPAL_INVESTIGATOR
affiliation: Peking Union Medical College Hospital
name: Shujie Wang, Doctor
role: PRINCIPAL_INVESTIGATOR
affiliation: Henan Cancer Hospital（The Affiliated Cancer Hospital Of ZhengZhou University)
name: Hu Zhou, Doctor
role: PRINCIPAL_INVESTIGATOR
affiliation: The First Affiliated Hospital of Soochow University
name: Ziqiang Yu, Doctor
role: PRINCIPAL_INVESTIGATOR
affiliation: The First Affiliated Hospital of USTC (Anhui Provincial Hospital)
name: Changcheng Zheng, Doctor
role: PRINCIPAL_INVESTIGATOR
affiliation: Nanfang Hospital, Southern Medical University
name: Jing Sun, Doctor
role: PRINCIPAL_INVESTIGATOR
affiliation: Xiangya Hospital of Central South University
name: Xielan Zhao, Doctor
role: PRINCIPAL_INVESTIGATOR
References: