V-IMMUNE: A Novel Immunoglobulin Therapy for Immunodeficiency

Introduction:

Immunoglobulin is used as a treatment for a variety of medical conditions, not only for its ability to combat infection as replacement therapy, but also for its anti-inflammatory and immunomodulatory effects. Immunoglobulins are primarily characterized by their antibody function, with various classes and subclasses that perform different roles. B cells are primarily responsible for the humoral adaptive immune response (antibody-mediated). Immunoglobulins, which are the molecules with antibody function, serve as the receptors of B cells, anchored to the membrane via a molecular complex composed of molecules that both anchor the immunoglobulin and promote signal transduction into the cell. This enables B cell activation, triggering a signaling cascade that leads to terminal differentiation into plasma cells or memory cells.

Inborn errors of immunity (primary immunodeficiencies - PIDs) represent a large, heterogeneous, and rapidly growing group of genetic diseases, primarily (but not exclusively) caused by loss- or gain-of-function germline mutations in genes associated with the immune response. Despite their individual rarity, inborn errors collectively affect a significant proportion of patients, with an estimated global prevalence of 1 in 1,200-2,000. They now comprise approximately 500 known genetic causes, subdivided into 10 categories listed in the 2022 classification by the International Union of Immunological Societies (IUIS), about two-thirds of which have been identified in the past decade. As evidence of the field's dynamic development, approximately 30 new diseases have been described per year in recent years.

Worldwide, the most common defects among PIDs-approximately 60%-involve impaired antibody production, with selective IgA deficiency and common variable immunodeficiency being the most prevalent. At least 80% of patients diagnosed with antibody deficiency receive IgG replacement therapy. PIDs can be an unrecognized underlying condition associated with autoimmune, allergic, and lymphoproliferative diseases and may therefore remain undiagnosed for many years. Patients diagnosed with B cell dysfunction and resulting antibody deficiencies require immunoglobulin G (IgG) replacement, a safe and effective therapeutic option for preventing infections in patients with PIDs.

Intravenous immunoglobin is used to treat a wide range of diseases. However, its approved indications can be divided into three main categories: primary and secondary antibody deficiencies, vertically transmitted HIV, chronic lymphocytic leukemia (CLL), immune thrombocytopenic purpura (ITP), chronic inflammatory demyelinating polyneuropathy (CIDP), severe disseminated infections, and graft-versus-host disease. It is recommended to initiate immunoglobulin replacement therapy in all patients who meet the diagnostic criteria for IgG hypogammaglobulinemia, whether they have agammaglobulinemia, common variable immunodeficiency (CVID), or IgG subclass deficiencies with functional antibody production impairment In this protocol, investigators discuss the use of a commercially available human polyvalent immunoglobulin product for intravenous use at 5% concentration, branded V-MMUNE, for the treatment of inborn errors of humoral immunity / primary immunodeficiencies involving impaired production of IgG class immunoglobulins by B lymphocytes.

Considering the relative unavailability of blood products, among which immunoglobulins are in the most critical category, the approval of new products in Brazil is of utmost importance due to the increasing need for this medication-even for well-defined indications such as hypogammaglobulinemia, whether primary or secondary, as well as neuropathies like Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), and hematologic conditions such as immune thrombocytopenic purpura. Several factors have contributed to this shortage, including increasingly stringent safety requirements; the difficulty in obtaining high-quality plasma that meets the standards of major regulatory agencies such as the FDA and EMA; the need to improve manufacturing processes; the reduction in the number of donors due to the COVID-19 pandemic; and the increased demand for IVIG at the beginning of the pandemic, when immunoglobulin was used as a therapeutic attempt for a then-unknown disease.

Therefore, the availability of new products, like V-IMMUNE produced by Virchow Laboratories in India, that are effective for the treatment of clearly defined indications and possess the necessary safety profile-ensuring minimal adverse reactions during and after clinical use-is essential.

The investigators present here a clinical trial for regulatory approval of a novel immunogloblin V-IMMUNE® in the Brazilian market for primary immunodeficiency.

Objectives

The objectives of the study are:

1. To evaluate the efficacy of the human normal immunoglobulin preparation V-IMMUNE® for patients with primary humoral immunodeficiency in preventing the rate of serious bacterial infection in 12 months compared to historical controls; 2. To evaluate the safety of the human normal immunoglobulin preparation V-IMMUNE® regarding the observed proportion of infusions with one or more temporally associated adverse events in patients with primary humoral immunodeficiency; 3. To evaluate the pharmacokinetics of intravenous V-IMMUNE® in patients with primary humoral immunodeficiency.

Methods:

Study Design This is a prospective, Phase III, open-label, non-randomized, multicenter, single-group study with a historical control for the regular administration of V-IMMUNE® via the intravenous route.

Recruitment Plan Recruitment will take place through 10 national reference immunology centers specialized in the treatment of primary immunodeficiency with intravenous immunoglobulin infusion. Patients who are already receiving regular intravenous immunoglobulin therapy and meet the eligibility criteria will be invited to participate in the study, switching from their current product to the investigational product (IP) for a duration of 12 months.

Recruitment Approach Patients who meet the inclusion criteria and are already receiving IgG treatment at the participating centers will be approached for inclusion in the VIP study. Once the informed consent form (ICF) is signed, the participant will begin receiving V-Immune® (On-Pharma) as per the study protocol.

As this is a single-group study, randomization will not be performed. Blinding Given that this is a single-group study and the eligible patients are already being treated with another commercially available immunoglobulin, which will be replaced by V-IMMUNE®, blinding is deemed unnecessary.

Experimental Intervention The Investigational Product (IP) is V-IMMUNE®, normal human immunoglobulin I.P. 5% (5g/100 mL), manufactured from qualified human plasma for intravenous use. Each vial contains Human Immunoglobulin 50 g/L, Maltose 100 g/L, and Water for Injection. The 5% Human Immunoglobulin solution for intravenous administration I.P. is a sterile, pyrogen-free preparation of normal human immunoglobulin in a single-dose form for intravenous infusion. Each 10 mL, 50 mL, and 100 mL contains 0.5 g, 2.5 g, and 5 g of normal human immunoglobulin, respectively, and is prepared from qualified human plasma using membrane filtration, combined chromatographic steps, and viral inactivation procedures. The IgA content does not exceed 2 mg/mL. The IgG subclass distribution is similar to that found in normal human serum.

The manufacturing process uses plasma collected from donors who are screened based on medical history, in accordance with regulatory authority guidelines. The blood is tested for mandatory infectious diseases. Only plasma that tests negative for HBsAg, HCV, and HIV antibodies is used in the process.

Normal Human Immunoglobulin I.P. 5% (5g/100 mL) V-IMMUNE® will be administered at a dose of 600 mg/kg every 3 weeks (+/- 3 days) via intravenous (IV) route at the infusion rate specified below, over a duration of 3 to 6 hours:

0.01 ml/kg/min 0-30 min, 0.02 ml/kg/min 31 to 45 min, 0.04 ml/kg/min 46 to 60 min and 0.06 ml/kg/min 61 min until the end of infusion.

Dose Escalation Dose escalation occurs gradually unless adverse events (AEs) occur. The dose is only increased if there is good tolerance, without the presence of adverse events. If an AE occurs, the infusion must be paused for 20 to 30 minutes. The use of loratadine, paracetamol, and ondansetron will be allowed. Exceptionally, another drug from the same class may be used, provided the pharmacokinetics study center is informed. Once the patient improves, the infusion is resumed at a reduced rate, returning to the initial infusion speed. The patient will be observed for 60 minutes after the infusion ends for clinical assessment and monitoring of potential adverse events .

Pre-medication Pre-medication prior to infusion of the investigational product: rapid infusion of 500 mL of 0.9% sodium chloride (NaCl) IV, diphenhydramine 50 mg IV, and hydrocortisone 200 mg IV, followed by the investigational product administered at progressively increasing infusion rates as described above. After infusion, 0.9% NaCl should be continued at 1 mL/kg/hour. The use of pre-medication is standard medical practice and is considered necessary for participant safety.

Rapid isotonic saline infusion before administration and slow isotonic saline infusion to maintain venous access for at least 30 to 40 minutes are necessary and standard practice in the administration of these blood products. Rapid crystalloid before infusion reduces the risk of headaches and aseptic meningitis post-administration, as well as the risk of thromboembolic events. Crystalloid administration after the investigational product infusion reduces the risk of serious and potentially life-threatening adverse events due to anaphylactic reactions by allowing for the rapid administration of IV medications in a potentially shocked patient, avoiding the need for emergency central venous access.

Pre-medication Summary:

Rapid infusion of 500 mL of 0.9% sodium chloride (NaCl) IV

Diphenhydramine\* 50 mg IV (adult); Pediatric: 1.25 mg/kg IV

Hydrocortisone\*\* 200 mg IV (adult); Pediatric: 3 mg/kg IV

After infusion: 0.9% NaCl at 1 mL/kg/hour for one hour After the initial three months, diphenhydramine and hydrocortisone may be discontinued.

Thromboembolism risk: use the slowest possible infusion rate

\* Administer 30 minutes before infusion.

\*\* Administer 30 minutes to 1 hour before infusion.

For individuals at risk of thromboembolism, the infusion rate must be kept as low as possible.

Thromboembolism risk factors include: advanced age, obesity, hypertension, diabetes mellitus, history of previous thromboembolic events, known acquired or congenital thrombophilic disorders, prolonged immobilization, severe hypovolemia, or increased blood viscosity.

Treatment intervals between administrations should remain constant throughout the study, provided that the IgG trough levels remain \>500 mg/L.

If body weight changes by more than 5% compared to baseline (screening visit), the dose will be adjusted to maintain a consistent mg/kg body weight dosage.

In the event of clinically significant hypotension and/or anaphylactic reactions, in addition to stopping the infusion and administering appropriate supportive care (which may include epinephrine, antihistamines, corticosteroids, supplemental oxygen, and volume expansion), and recording the incident in the CRF as an AE, the participant may be withdrawn from the study at the investigator's discretion. In such cases, participants may, if they wish, complete follow-up visits

Contraindications and Precautions Related to the IP Normal Human Immunoglobulin for Intravenous Administration I.P. 5% is contraindicated in patients

• Severe and non-severe bacterial infections [Срок оценки: 12 months]
• Number of patients with 0, 1, 2, etc., severe infections [Срок оценки: 12 months]
• Number of adverse events by body systems [Срок оценки: 12 months]
• Time to first infection [Срок оценки: 12 months]
• Nadir of pre-infusion total IgG level [Срок оценки: 3 weeks]
• Nadir of pre-infusion total IgG level in children aged 2 to <16 years [Срок оценки: 3 weeks after the fifth infusion]
• Number of any severe or non-severe infection [Срок оценки: 12 months]
• Infection resolution time [Срок оценки: 12 months]
• Use of antibiotics [Срок оценки: 12 months]
• Hospitalizations due to infections [Срок оценки: 12 months]
• Episodes of fever [Срок оценки: 12 months]
• Number of days absent from school or work [Срок оценки: 12 months]