Phase Ib Clinical Study to Evaluate the Safety and Tolerability of VSA012 Injection in Paroxysmal Nocturnal Hemoglobinuria

A Phase Ib Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Preliminary Efficacy of VSA012 Injection in Subjects With Paroxysmal Nocturnal Hemoglobinuria Who Are Complement Inhibitor Naïve or Have Not Received Complement Inhibitor Recently and Have Persistent Anemia Despite Previous Stable Use of C5 Complement Inhibitor

The complement system is an important component of the innate immune system. Abnormal activation, inadequate regulation and control of the complement system, as well as impaired and dysfunctional effector functions, underlie complement mediated diseases including PNH. VSA012 targeting complement system has the potential to treat a variety of diseases associated with abnormal activation of the complement system.The purpose of VSA012-1002 is to evaluate the safety, tolerability, pharmacokinetic, pharmacodynamics and efficacy of VSA012 Injection in subjects with PNH.

Inclusion and Exclusion Criteria for Groups 1-4

• Participants voluntarily participate in this clinical study, and voluntarily sign the ICF;

• BMI ≥ 18.0 kg/m2; male or female; 18 to 75 years of age;

• Confirmed diagnosis of PNH by clinical manifestation and flow cytometry; granulocyte clone size ≥ 10%;

• Presence of one or more of PNH-related signs or symptoms within 3 months prior to screening;

• Hb < 100 g/L;

• LDH value > 1.5 × ULN;

• One of the following criteria for prior drug therapy for PNH must be met:

  1. Having never received any complement inhibitor therapy;
  2. Having received C5, C3, or CFB complement inhibitors and having discontinued the complement inhibitor for more than 5 half-lives or 3 months prior to screening;

• Participants are willing to receive meningococcal vaccine and pneumococcal vaccine at least 14 days prior to dosing.

Inclusion and Exclusion Criteria for Groups 5

• Participants voluntarily participate in this clinical study, and voluntarily sign the ICF;
• BMI ≥ 18.0 kg/m2; male or female; 18 to 75 years of age;
• Confirmed diagnosis of PNH by clinical manifestation and flow cytometry; granulocyte clone size ≥ 10%;
• Participants who have been on a stable dose and interval of a C5 complement inhibitor (approved locally) for at least 3 months prior to the first dose of VSA012;
• Within the 3 months prior to screening, have a documented Hb level of < 105 g/L while on C5 complement inhibitor therapy;
• Hb < 105 g/L;
• Participants are willing to receive meningococcal vaccine and pneumococcal vaccine at least 14 days prior to dosing.

Exclusion Criteria for Groups 1-4

• History of hypersensitivity to VSA012 or its excipients;

• Use of any complement inhibitors within 3 months prior to screening

• Use of any targeted small interfering RNA (siRNA) within 18 months prior to screening, or any antisense oligonucleotide molecule within 6 months prior to screening;

• Supportive care for PNH does not meet the stable-dose requirements:

• Participants have infections;

• Laboratory tests meet the following criteria:

  1. Reticulocyte count < 100 × 109/L;
  2. Platelet count < 30 × 109/L;
  3. Neutrophil count < 0.5 × 109/L;
  4. Creatinine clearance < 30 mL/min (calculated by the Cockcroft-Gault formula);

Exclusion Criteria for Groups 5

• History of hypersensitivity to VSA012 or its excipients;

• Use of any targeted small interfering RNA (siRNA) within 18 months prior to screening, or any antisense oligonucleotide molecule within 6 months prior to screening;

• Supportive care for PNH does not meet the stable-dose requirements:

• Participants have infections;

• History of splenectomy;

• Previous suspected/confirmed hereditary complement deficiency;

• History of recurrent invasive infections with capsular bacteria, e.g., meningococcus or pneumococcus;

• Laboratory tests meet the following criteria:

  1. Reticulocyte count < 100 × 109/L;
  2. Platelet count < 30 × 109/L;
  3. Neutrophil count < 0.5 × 109/L;
  4. Creatinine clearance < 30 mL/min (calculated by the Cockcroft-Gault formula);