A Study of HBM9161 in NMOSD Patients

Study Overview
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Brief Summary
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Primary Objectives:To investigate the safety and tolerability of HBM 9161 in patients with attack of NMOSD in China

Detailed Description
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This is an open-label, dose exploration study.The investigational drug is HBM9161 injection, and the indication is NMOSD. HBM9161(HL161BKN) is a human monoclonal antibody. HBM9161 targets the neonatal Fc receptor (FcRn) . By blocking the FcRn IgG-Fc binding site and accelerating the degradation of IgG, it can significantly reduce the total IgG level in blood (including pathological IgG).The serum aquaporin 4 antibody (AQP4-IgG) associated with NMOSD is a pathological IgG, so the combination of standard of care which is intravenous methylprednisolone (ivMP) with HBM9161 is expected to rapidly reduce AQP4-IgG levels. Two dose groups (340 mg and 680 mg) were planned, and each dose group plans to enroll approximately 6 subjects. All subjects are weekly administered the HBM9161 by subcutaneous injection for a period of 4 weeks, together with standard of care which is of intravenous methylprednisolone (ivMP) by subcutaneous for a period of 4 weeks. The study will investigate the safety, and tolerability, pharmacodynamics and efficacy of HBM 9161 in patients with attack of NMOSD in China.

Official Title
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Safety, Tolerability, Pharmacodynamics and Efficacy of HBM9161 Weekly Subcutaneous Administration in Patients With Neuromyelitis Optica Spectrum Disorders (NMOSD) in China

Conditions
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NMO Spectrum Disorder

Intervention / Treatment
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* Drug: HBM9161 Injection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: In visit 1, Male or female aged ≥ 18 years. Patient with NMOSD as defined by 2015 NMOSD diagnostic criteria by IPND (International Panel for NMO Diagnosis). Core clinical manifestations characterized by new acute optic neuritis and/or transverse myelitis. A clinical event is defined as an episode of inflammation in the spinal cord and/or optic nerve leading to neurologic deficits which can be identified by physical examination and not attributable to another disease process. The EDSS score should be ≥ 2.5 and ≤7.5 at visit 1. AQP4-IgG is positive at visit 1 or had AQP4-IgG positive medical records before visit 1. Be able to recognize English letters. Patients should be on stable treatment of the following medications before screening (if anyone had a stable treatment ): Immunosuppressant or immunomodulatory drugs (for example, azathioprine, cyclophosphamide, mycophenolate mofetil, tacrolimus, methotrexate and so on) must be stable for at least 8 weeks before screening and keep stable during study • Corticosteroids At screening, the treatment dose must be stable for at least 1 month. • If patients accepted plasmapheresis or IVIg treatment, the last treatment dose/procedure must be finished at least 4 weeks ago before screening Exclusion Criteria: No acute optic neuritis and/or transverse myelitis symptoms or signs. Severe NMOSD which may require plasmapheresis or intravenous immunoglobulin (IVIG) treatment, in opinion of investigator, very soon. Have received plasmapheresis or IVIG treatment, the last treatment dose/procedure is less than 4 weeks before visit 1. Have known autoimmune diseases other than NMOSD that would interfere with efficacy assessment or participation in this study (such as uncontrolled thyroid disease or severe rheumatoid arthritis), or have any comorbid diseases which would interfere with the efficacy evaluation of HBM9161 on NMOSD. Have received rituximab or other anti-CD20 drugs treatment within 6 months before visit 1. Have been used any monoclonal antibodies or research drugs for immunomodulatory effects within 3 months before visit 1 or within 5 half-life periods of the drug. Females who are pregnant or lactating. Patients who can't tolerate or have contraindication to high dose intravenous methylprednisolone per Investigator's opinion. Have active infection at screening, or recent serious infection (i.e., requiring intravenous antimicrobial therapy or hospitalization) within 8 weeks before screening; history of or existing infection of human immunodeficiency virus(HIV), hepatitis C virus (HCV), or Mycobacterium tuberculosis. Patients must have negative test results for HCV antibody, HIV 1 and HIV 2 antibodies, and a mycobacterium tuberculosis test (test method to be determined) at visit 1. Patients have positive test result for HBsAg; or HBsAg negative meanwhile HBcAb positive and HBV-DNA level>2000IU/mL. Serum total IgG <700mg/dL at visit 1. Absolute neutrophil count <1500个/mm3 at visit 1 and/or visit 2 Patients with acute liver function impairment (e.g., hepatitis) or severe liver cirrhosis (Child-Pugh Score, Class C) Any malignant tumor.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Interventional Model Description: Dose exploration study. Two dose groups (340 mg and 680 mg) were planned, 6 subjects at most for 340 mg group and 6 to 12 subjects for 680mg group. Each subject will only participate in one dose group. Escalation to the next dose level decided by PIs and sponsor after evaluating safety data and PD data for lower dose group.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental: HBM9161, 340mg<br>HBM 9161 injection, 340mg, weekly administered by subcutaneous for a period of 4 weeks. | Drug: HBM9161 Injection<br>* Subcutaneous injection; Weekly administered for a period of 4 weeks. All subjects are treated with the testing drug, add on intravenous methylprednisolone (ivMP) with gradually reduce the dose then to oral prednisone. After the administration of the testing drug, if the subject's symptoms get worsen, a rescue therapy need to be adopted as based on Investigator's judgement, the testing drug injection should be discontinued.<br>|
| Experimental: Experimental: HBM9161, 680mg<br>HBM 9161 injection, 680mg, weekly administered by subcutaneous for a period of 4 weeks. | Drug: HBM9161 Injection<br>* Subcutaneous injection; Weekly administered for a period of 4 weeks. All subjects are treated with the testing drug, add on intravenous methylprednisolone (ivMP) with gradually reduce the dose then to oral prednisone. After the administration of the testing drug, if the subject's symptoms get worsen, a rescue therapy need to be adopted as based on Investigator's judgement, the testing drug injection should be discontinued.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of treatment related adverse events (AEs) | Number of treatment related adverse events (AEs) | 189 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immunoglobins changes from baseline to week 27 | Change of concentration of immunoglobins in mg/ml overtime after administration of HBM9161 from baseline to week 27 | 189 days | 
| Neurological Disability changes from baseline to week 27 | Neurological Disability changes from baseline to week 27 as measured by Expanded Disability Scale Score (EDSS, Score 0-10, higher means a worse outcome) | 189 days | 
| Low Contrast Visual Acuity (LCVA) changes from baseline to week 27 | Low Contrast Visual Acuity (LCVA) changes from baseline to week 27 as measured by Sloan Low Contrast Letter Scale (SLCLS Letter, Score 0-70, higher means a better outcome) | 189 days | 
| Patient reported improvement changes from baseline to week 27 | Patient reported improvement changes from baseline to week 27 as measured by Patient Global Impression-Improvement (PGI-I, Score 1-7, higher means a worse outcome) | 189 days | 
| Percentage of patients who received rescue therapy | Percentage of patients who received rescue therapy | 189 days | 
| Percentage of patients who have relapse | Percentage of patients who have relapse | 189 days | 
| Walking ability changes from baseline to week 27 | Walking ability changes from baseline to week 27 as measured by time used for 25-foot Walk (applicable for patients who are able to walk) | 189 days | 
| The seropositive rate of anti-HBM9161 antibody after treatment | Evaluation of the seropositive rate of anti-HBM9161 antibody after treatment | 189 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NMOSD