Study to Assess the Safety, Tolerability, Efficacy, PK, PD and POC of Intravenous ANX005 in Patients With wAIHA

Phase 1

Conditions: Warm Autoimmune Hemolytic Anemia
Therapeutic area: Diseases [C] - Blood and lymphatic diseases [C15]
MedDRA version: 20.0Level: LLTClassification code 10003825Term: Autoimmune hemolytic anemiaSystem Organ Class: 100000004851

Registration Number: EUCTR2020-003675-18-FR

Lead Sponsor: Annexon, Inc.

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Authorised-recruitment may be ongoing or finished

Sex: All

Target Recruitment: 12

Inclusion Criteria

Patients must meet ALL the following criteria to be eligible to participate in the study:
1. Male or female =18 years of age on the day of signing informed consent
2. Diagnosis of wAIHA at least 3 months prior to screening and have relapsed or are refractory to standard of care (SoC) therapy (eg, immunosuppressants, corticosteroids, mAbs such as rituximab, or splenectomy)
3. Hemoglobin level =10.0 g/dL (pre-transfusion) at screening with no alternative explanation for anemia apart from wAIHA
4. Positive DAT =1+ for C3d and IgG within 6 months prior to dosing
5. Evidence of classical complement pathway activation by at least one of the following within 6 months prior to dosing :
a. Serum complement component 4 (C4) below the lower limit of normal
b. CH50 below the lower limit of normal (LLN)
c. Complement component deposition on the cell surface assessed by flow cytometry
6. Evidence of active hemolysis at screening based on at least one of the following:
a. LDH above the upper limit of normal (ULN)
b. Indirect bilirubin above the ULN
c. Haptoglobin below the LLN
7. If on corticosteroids, patients must be receiving a stable dose =1 mg/kg prednisone or equivalent. Tapering of corticosteroids is permitted during the screening period, but the patient’s dose must be stable for at least 14 days prior to ANX005 dosing. Enrolled patients should remain on a stable prescribed dose throughout the study. For patients who are not currently receiving corticosteroids, use should be discontinued within 30 days prior to dosing.
8. If on immunosuppressants (eg, azathioprine, mycophenolate mofetil, cyclosporine) must be on stable dose for at least 4 weeks prior to dosing.
9. Patients must have been previously vaccinated for encapsulated bacteria within 5 years prior to screening or be willing to receive prophylaxis against infections with encapsulated bacteria via vaccination and/or the use of prophylactic antibiotics in accordance with local standards of practice and/or guidelines.
10. If female, must be either postmenopausal (no menses for at least 12 months without an alternative medical cause) or surgically sterilized; OR if a woman of childbearing potential (WOCBP), patient must use a highly effective (ie, failure rate of <1%) method of contraception during the study and for 3 months after the last infusion with study medication.
11. If male, must agree to either abstain from heterosexual intercourse as the preferred and usual lifestyle (ie, abstinent on a long term and persistent basis) and agree to remain abstinent OR use a male condom during the study and for at least 3 months after the last infusion with study medication; and should also be advised of the benefit for a female partner to use a highly effective (ie, failure rate of <1%) method of contraception
12. Able to comply with the requirements of the study and complete the full sequence of protocol-related doses, procedures, and evaluations
13. Ability to understand and provide written informed consent
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 10
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 2

Exclusion Criteria

Patients must NOT meet any of the following criteria to be eligible to participate in the study:
1. Active lymphoma, lymphoproliferative disorder, or other malignancy requiring therapy and/or not clinically stable or in remission for at least 3 months prior to screening.
2. Elevated aspartate aminotransferase or alanine aminotransferase levels > 2.5 times the upper limit of normal at screening
3. Platelet count < 30 × 109/L at screening
4. History of cold agglutinin disease or IgM cold agglutinin titer >1:64
5. History of solid organ, bone marrow, or stem cell transplantation
6. History of splenectomy within the 90 days prior to screening
7. Received rituximab or other B cell depleting monoclonal antibody (eg, daratumumab) <90 days prior to screening
8. Clinically significant, ongoing illness or medical condition, including mental illness, suicide attempt, seizures, cardiovascular disease, malignancy, or a medical history that would jeopardize the safety of the patient, limit participation, or compromise the interpretation of the safety data derived from the patient
9. History of a systemic autoimmune disorder (eg, lupus) or primary immunodeficiency disorder (eg, common variable immune deficiency)
10. History of meningitis or septicemia within the past 2 years
11. Clinically significant infection (ie, viral, including symptomatic or asymptomatic SARS-CoV2 [COVID-19], bacterial, fungal, or mycobacterial) that required medical intervention (not including antibiotic prophylaxis) within 1 month prior to screening
12. Known genetic deficiencies of the complement cascade system
13. Treatment with an investigational therapeutic agent within 30 days or five half-lives, whichever is longer, prior to screening
14. Active alcohol or substance abuse or any other reason that makes it unlikely that the patient will comply with study procedures
15. Females who are pregnant or breastfeeding. Note: To be eligible, WOCBP must have a negative pregnancy test at screening (serum) and Day 1 (urine).
16. Hypersensitivity to ANX005 or any of the excipients in the ANX005 drug product
17. Hypersensitivity to or previous allergic reaction to the active substance or to any of the excipients in any of the immunizations required for this study
18. History of previous sensitivities or allergic or anaphylactic reactions to previous IV medication including, but not limited to, monoclonal antibodies
19. Positive serology for human immunodeficiency virus (HIV) 1 or 2 at screening
20. Evidence of hepatitis C virus (HCV) antibody at screening requires reflex testing for HCV ribonucleic acid (RNA). Patients with positive HCV RNA viral load at screening will be excluded. Patients with positive HCV antibody, but negative HCV RNA viral load are eligible but should be monitored throughout the study
21. Evidence of active or prior hepatitis B virus (HBV) infection. Patients with positive hepatitis B surface antigen (HBsAg) at screening are excluded from the study. Patients with positive HBV core antibody and deoxyribonucleic acid (DNA) viral load are excluded from the study
22. History of intravenous immunoglobulin (IVIg) treatment within 90 days prior to dosing
23. History of plasmapheresis or immunoadsorption treatment within 60 days prior to dosing
24. Received any complement inhibitor (eg, eculizumab, berinert) within 90 days or 5 half-lives, whichever is longer, prior to dosing
25. Body weight less than 50 kg or greater than 100 kg

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: The primary objective of this repeat dose Phase 2 study are as follows:<br>• To evaluate the safety and tolerability of two once-weekly intravenous infusions of 100 mg/kg ANX005 in patients with wAIHA<br>• To evaluate the clinical effect of two once-weekly intravenous infusions of 100 mg/kg ANX005 in patients with wAIHA;Secondary Objective: The secondary objectives of the study are as follows:<br>• To evaluate the pharmacokinetic (PK) profile of ANX005 in subjects with wAIHA<br>• To evaluate the effect of ANX005 on classical complement pathway inhibition as measured by complement system related biomarkers in subjects with wAIHA;Primary end point(s): • Number and percent of patients experiencing treatment-emergent adverse events (TEAEs)<br>• Change from baseline in hemoglobin over time up to Day 71<br>• Change from baseline in biomarkers of hemolysis (reticulocyte count, haptoglobin, LDH, total and indirect bilirubin) over time up to Day 71;Timepoint(s) of evaluation of this end point: 10 weeks

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): • ANX005 plasma concentration profiles and PK parameters such as AUC, Cmax, Tmax, accumulation ratio, t1/2, ?z, CL and Vss<br>• Inhibition of classical complement activity as measured by serum CH50 from baseline over time up to Day 71<br>• Change and percent change from baseline in serum C4 concentrations over time up to Day 71<br>• Change and percent change from baseline in serum free C1q concentrations over time up to Day 71;Timepoint(s) of evaluation of this end point: 10 weeks

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