A PHASE 3, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY, WITH A SAFETY AND DOSE CONFIRMATION RUN-IN PERIOD, TO EVALUATE THE EFFICACY AND SAFETY OF OBEXELIMAB IN PATIENTS WITH WARM AUTOIMMUNE HEMOLYTIC ANEMIA (SAPHIARE)

Trial ID: 2022-501005-12-00
Protocol: ZB012-03-002
Sponsor: Zenas Biopharma (USA) LLC

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Diseases & Conditions

Warm autoimmune haemolytic anaemia

Objectives

The primary objective of this Phase 3, multicenter, randomized, double-blind, placebo-controlled study is to evaluate the **safety** and tolerability of weekly subcutaneous administration of obexelimab in patients with **warm autoimmune hemolytic anemia** (wAIHA). Additionally, the study aims to assess the clinical benefit of obexelimab on anemia in these patients. This is clinically relevant as wAIHA is a condition characterized by the premature destruction of red blood cells, leading to anemia, and effective management of this condition is crucial for improving patient outcomes.

Secondary objectives include:

Part A: To evaluate the clinical benefit of weekly SC administration of obexelimab on other measures of disease activity in patients with wAIHA.
Part B: To evaluate the clinical benefit of weekly SC administration of obexelimab on other measures of disease activity and to assess the safety and tolerability in patients with wAIHA.

Participants

The clinical trial involves a total of **13 participants** diagnosed with **warm autoimmune hemolytic anemia (wAIHA)**. The study population includes both **male and female** subjects aged **18 years and older**. Participants were selected based on specific inclusion criteria, such as having a confirmed diagnosis of wAIHA for at least three months and having failed at least one prior treatment regimen. The trial does not specify any particular lifestyle considerations such as diet or physical activity. Participants are required to have a stable health status, with screening parameters like neutrophil count, serum albumin, and serum calcium concentrations within normal ranges. The trial includes individuals who may have undergone splenectomy or have other autoimmune disorders, provided their conditions are stable. The study population is not limited to any specific vulnerable groups, although it includes individuals who are capable of providing informed consent and complying with study requirements.

Plans and Procedures

The clinical trial is designed to evaluate the **efficacy** and **safety** of **obexelimab** in patients with **warm autoimmune hemolytic anemia** (wAIHA). This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled study, which includes a safety and dose confirmation run-in period. The trial is structured into three parts: Part A, the Safety and Dose Confirmation Run-in Period (SRP); Part B, the Randomized Control Period (RCP); and Part C, the Open-Label Extension (OLE) Period. The estimated duration of the trial is from October 2023 to July 2027.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis of wAIHA, and previous treatment history. The trial will include follow-up visits to monitor the safety and clinical benefit of weekly subcutaneous administration of obexelimab. The end-of-study visit will assess the overall outcomes and any adverse events experienced by the participants. The expected length of participant involvement varies depending on the part of the trial they are enrolled in, with the possibility of continuing into the OLE Period if they complete the SRP or RCP.

Participants may be terminated early from the study if they experience significant adverse events, become pregnant, develop a malignancy, or if the investigator deems it necessary for patient safety. The primary endpoints include the incidence of adverse events, the proportion of patients achieving a durable hemoglobin response, and the time in hemoglobin response. Secondary endpoints focus on changes in fatigue scores, the use of rescue therapy, and the incidence of anti-obexelimab antibodies. The trial aims to provide comprehensive data on the therapeutic potential of obexelimab in managing wAIHA.

Treatment

The clinical trial involves the administration of **Obexelimab**, an experimental medication, to evaluate its efficacy and safety in patients with warm autoimmune hemolytic anemia (wAIHA). **Obexelimab** is provided in the form of an **injection** and is administered via the **subcutaneous route**. The dosage is set at a maximum of 250 mg per day, with a total maximum dose of 250 mg over the treatment period. The administration schedule involves weekly injections, and the treatment period is limited to one week. **Obexelimab** is a protein-based therapeutic agent developed by Zenas Biopharma (USA) LLC, and it is designated as an orphan drug under the designation number EU/3/17/1962.

In addition to the experimental treatment, a **placebo** is used as a comparator in this double-blind, placebo-controlled study. The placebo is a sterile solution intended for subcutaneous injection, mirroring the administration route of **Obexelimab**. The placebo serves to maintain the study's blinding and to provide a baseline for evaluating the clinical benefits of the experimental treatment. The placebo does not contain any active pharmaceutical ingredients and is used to ensure that any observed effects can be attributed to the active treatment.

Efficacy

The efficacy of Obexelimab in patients with **Warm Autoimmune Hemolytic Anemia (wAIHA)** will be assessed through a series of primary and secondary endpoints. The primary efficacy endpoints include the proportion of patients achieving a hemoglobin (Hgb) level of ≥ 10 g/dL and an increase of ≥ 2 g/dL from baseline, without the use of blood transfusion or glucocorticoid (GC) rescue therapy, on or after Week 8. Additionally, the proportion of patients who achieve a durable Hgb response, defined as maintaining the specified Hgb levels on at least 3 of 4 consecutive visits starting at Week 12, will be evaluated through Week 24.

Secondary endpoints will assess changes from baseline in various parameters, including the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) score through Week 24, and the proportion of patients with no use of blood transfusion or GC rescue therapy through Week 24. Other secondary measures include the time to achieve the specified Hgb levels, changes in lactate dehydrogenase (LDH), haptoglobin, and indirect bilirubin levels, as well as the incidence of anti-obexelimab antibodies and changes in circulating immune cell counts and immunoglobulin levels.

Efficacy assessments will be conducted at specified timepoints, including Week 8, Week 12, and Week 24, using validated laboratory tests and patient-reported outcomes. The analysis will focus on the clinical benefit of weekly subcutaneous administration of Obexelimab, with data collected and analyzed according to the trial protocol to ensure robust and reliable results.

Inclusion and Exclusion Criteria

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Inclusion Criteria

PARTS A AND B: INCLUSION CRITERIA 1. Males and females ≥ 18 years of age at the time of signing the informed consent
Diagnosed with wAIHA for at least 3 months and currently receiving treatment for wAIHA or have previously received treatment for wAIHA (treatment-naive patients are not eligible)
Diagnosis of primary or secondary wAIHA as documented by a positive DAT specific for anti-IgG or anti-IgA
Failed at least 1 prior wAIHA treatment regimen, including steroids, rituximab, azathioprine, cyclophosphamide, cyclosporine, mycophenolate mofetil, danazol, vincristine, erythropoiesis-stimulating agents, or splenectomy (folate, iron, or other supplements do not fulfill this criterion). Failure is defined as a drop in Hgb of ≥ 1 g/dL and an increase in LDH of ≥ 1.5 × upper limit of normal (ULN) after a minimum of 4 weeks of GC therapy, or 3 months of immunosuppression therapy, respectively.
For the SRP (Part A) only, if on prednisone/prednisolone, the dose may not exceed 30 mg/day and must have been stable for at least 4 weeks prior to enrollment. Patients must remain on the stable dose throughout the SRP, except for patients on doses of >20 mg to ≤ 30 mg/day who may taper to no less than 20 mg/day and remain on a stable dose thereafter once they have achieved the primary endpoint and have a Hgb response on 2 consecutive in-clinic visits. For the RCP (Part B), if on prednisone/prednisolone, the dose may not exceed 20 mg/day and must have been stable for at least 4 weeks prior to randomization and remain stable throughout the RCP
If receiving immunosuppressants, must have been on a stable dose for at least 12 weeks prior to enrollment (SRP) or randomization (RCP) and remain on a stable dose throughout the SRP or RCP. Allowed concomitant immunosuppressants are azathioprine, mycophenolate mofetil/mycophenolic acid, cyclosporine, and cyclophosphamide
Hgb ≥ 7 to < 10 g/dL
At least one sign or symptom of anemia as assessed by the investigator at screening
Screening platelet count ≥ 50,000 mm3
Screening neutrophil count ≥ 1,000 mm3
Screening serum albumin and serum calcium concentrations within the normal range
Screening total serum IgG of ≥ 400 mg/dL
Screening creatine kinase value < 2 × ULN
Patients with a history of splenectomy must be at least 4 months post resection prior to enrollment (SRP) or randomization (RCP) and must be vaccinated as per country-specific immunization schedules
Patients with autoimmune disorders (e.g., systemic lupus erythematosus, rheumatoid arthritis) may be eligible if they are receiving stable treatment (no changes in disease- related concomitant medications), and the severity of disease has been stable for at least 4 months prior to enrollment (SRP) or randomization (RCP)
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Females not pregnant (see Appendix 4), not breastfeeding, and for whom at least one of the following conditions applies: a. Not of childbearing potential, as defined in Appendix 4 OR b. FOCBP with a negative serum pregnancy test at screening and a negative urine pregnancy test prior to the first dose of study drug and agreement to follow the contraceptive guidance in Appendix 4 for the duration of the study and for at least 8 weeks after the last administration of study drug c. Agree to refrain from egg donation until at least 8 weeks after the last dose of study drug
Males for whom the following conditions apply: a. Agree to (i) abstain from intercourse or (ii) use contraception (as detailed in Appendix 4) for the duration of the study and for at least 8 weeks after the last dose of IMP, or (iii) be surgically sterile for the duration of the study AND b. Agree to refrain from donating sperm for the duration of the study and for at least 8 weeks after the last dose of IMP
Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol
PART C: OLE PERIOD INCLUSION CRITERIA 1. Completed the Week 24 SRP or RCP visit 2. Have not had IMP discontinued due to any of the following safety reasons: a. Pregnancy b. Malignancy c. Hypersensitivity to IMP d. Determination that the patient was ineligible for the SRP and RCP e. For any reason deemed necessary by the investigator for patient safety 3. Have not discontinued from IMP due to unblinding of a patient 4. FOCBP must have a negative serum pregnancy test prior to enrollment in the OLE Period 5. Have not received a transfusion within 2 weeks prior to first dose in the OLE Period 6. Not receiving more than 2 concomitant medications for the treatment of wAIHA, excluding vitamins or other supplements, at the time of enrollment in the OLE Period 7. Patients must receive first dose of obexelimab in the OLE Period within 14 days of the Week 24 SRP/RCP visit 8. Willing to comply with all study protocol procedures and complete all study visits

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Exclusion Criteria

PARTS A AND B: EXCLUSION CRITERIA 1. Have cold antibody AIHA, cold agglutinin syndrome, mixed type (i.e., warm and cold) AIHA, or paroxysmal cold hemoglobinuria
Have any other associated cause of hereditary or acquired hemolytic anemia
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Received a transfusion within 2 weeks prior to enrollment (SRP) or randomization (RCP)
Use of B cell–depleting, B cell–targeted, or other biologic immunomodulatory agents within the 6 months prior to enrollment (SRP) or randomization (RCP). Patients who received B cell–targeted therapy within 6 to 12 months prior to randomization must have a B cell count at screening that is within the laboratory reference range, as measured by the central laboratory
Received IV Ig or epoetin alfa within 6 weeks prior to enrollment (SRP) or randomization (RCP). The patient may be re-screened after the exclusionary period of 6 weeks has passed
Receiving more than 2 concomitant medications for the treatment of wAIHA, excluding vitamins or other supplements, at the time of screening
Received an investigational treatment or direct medical intervention in another clinical study within 12 weeks or < 5 half-lives of the investigational treatment, whichever is shorter, prior to screening
Received live vaccine or live therapeutic infectious agent within the 6 weeks prior to enrollment (SRP) or randomization (RCP)
Evidence of active tuberculosis (TB) or at high risk for TB based on at least one of the following: a. History of active TB or latent TB, unless completion of treatment according to local guidelines is documented b. Positive, indeterminate, or invalid interferon-gamma (IFNγ) release assay results at screening, unless treatment is documented. Patients with an indeterminate test result can repeat the test once either centrally or locally, but if the repeat test is also indeterminate, the patient is excluded c. Signs of symptoms that could represent active TB d. Chest radiograph, computed tomography scan, or magnetic resonance imaging that suggests possible diagnosis of TB
History or evidence of a clinically unstable/uncontrolled disorder, condition, or disease (including, but not limited to, cardiopulmonary, oncologic, renal, hepatic, metabolic, hematologic, psychiatric, active infection), that, in the opinion of the investigator, would pose a risk to patient safety or interfere with the study evaluations, procedures, or completion
Known allergy to mAb therapy
Known hypersensitivity to dextran or components of dextran
Active infection (e.g., pneumonia, biliary tract infection, diverticulitis, Clostridium difficile infection) that requires parenteral or oral anti-infectives and/or hospitalization, and/or is assessed as serious/clinically significant by the investigator, within 8 weeks prior to screening. Patients may be re-screened after the 8-week exclusionary period has passed
Chronic infection (e.g., bronchiectasis, chronic osteomyelitis, chronic pyelonephritis) or requiring chronic treatment with anti-infectives (e.g., antibiotics, antivirals)
Confirmed or suspected clinical immunodeficiency syndrome not related to treatment of wAIHA, or has a family history of congenital or hereditary immunodeficiency, unless confirmed absent in the patient
Acute hepatitis B infection (hepatitis B surface antigen-positive), active hepatitis C virus (HCV), or HIV infection. Patients will be excluded from the study if they have a positive test for active hepatitis B through detection of (a) hepatitis B surface antigen or (b) hepatitis B core antibody. In Japan, patients will be excluded if there is detection of (a) hepatitis B surface antigen or (b) hepatitis B surface antibody or (c) hepatitis B core antibody. Patients with a history of HCV will be excluded in the study unless there is documentation of a negative HCV ribonucleic acid level in the serum at 12 weeks or longer after the completion of HCV therapy
Intend to become pregnant, breastfeed, or are planning egg or sperm donation during the study or within 8 weeks after the last dose of study drug
Current alcohol/substance abuse/dependence, a history of alcohol/substance abuse/dependence within the 12 months prior to enrollment (SRP) or randomization (RCP), or, in the investigator’s opinion, there is evidence of ongoing alcohol/substance abuse/dependence
Major surgery (surgery requiring hospitalization ≥ 3 days or with a high risk of re-bleeding) within 4 months prior to enrollment (SRP) or randomization (RCP) or have plans for or have been scheduled for any elective surgery or major dental procedure during the study
Have a history of a major organ transplant (e.g., heart, lung, kidney, liver) or hematopoietic stem cell/marrow transplant
Malignancy within 5 years of enrollment (SRP) or randomization (RCP)
Commitment to an institution by virtue of an order issued either by the judicial or the administrative authorities