A Phase 3, Randomized, Double-blind, Placebo-controlled Study of Felzartamab in Adults with IgA Nephropathy (299IG301 / PREVAIL)

The primary objective of this study is to evaluate the efficacy of felzartamab compared to placebo on proteinuria in participants with Immunoglobulin A nephropathy (IgAN). Proteinuria represents a critical marker of disease activity and progression in IgAN, making its reduction clinically relevant for assessing therapeutic benefit and potential renal protection.

The secondary objectives include:

• Evaluation of the efficacy of felzartamab compared to placebo on kidney function in participants with IgAN, representing the main secondary objective focused on preservation of renal functional capacity.

• Assessment of the efficacy of felzartamab compared to placebo on additional clinical endpoints to provide comprehensive evaluation of therapeutic effects beyond the primary measure.

• Characterization of the pharmacokinetics and immunogenicity of felzartamab to establish the drug exposure profile and potential immune responses to the therapeutic agent.

This clinical trial enrolled a total of **353 participants** diagnosed with **IgA nephropathy**. The study population included both **male and female** subjects comprising **adults** and **elderly** individuals. Participants were required to have a **biopsy-confirmed diagnosis** of IgA nephropathy within the past 10 years prior to enrollment, with a more recent confirmation required for those with **type 2 diabetes mellitus**. The trial population was selected based on specific renal function parameters, requiring an **estimated glomerular filtration rate (eGFR)** of at least 30 mL/min/1.73m² at screening, calculated using the 2021 chronic kidney disease epidemiology creatinine formula. Participants were required to demonstrate significant **proteinuria** of at least 1.0 gram per day or a urine protein-to-creatinine ratio of at least 0.8 gram per gram. All enrolled subjects needed to be clinically stable on a maximally tolerated or maximally approved dose of **angiotensin-converting enzyme inhibitors** or **angiotensin receptor blockers** for at least 12 weeks prior to screening, unless intolerant to these medications. Participants could also be using **sodium-glucose cotransporter-2 inhibitors**, **endothelin receptor antagonists**, dual endothelin angiotensin receptor antagonists, or **mineralocorticoid receptor antagonists** provided the dosing remained stable throughout the study period. The trial included a vulnerable population subset as part of its enrollment criteria.

This is a Phase 3, randomized, double-blind, placebo-controlled clinical trial evaluating the efficacy and safety of felzartamab in adults with IgA nephropathy. The primary objective is to assess the efficacy of felzartamab compared to placebo on proteinuria in participants with this condition. The study employs a randomized design where participants will be assigned to receive either the investigational product or placebo while maintaining stable background therapy.

The investigational medicinal product, felzartamab, is administered as a lyophilized powder via intravenous administration at a maximum daily dose of 1625 mg, with a maximum total dose of 14625 mg over the treatment period. The maximum treatment period is 20 days. Participants will also receive 0.9% saline as an auxiliary product. Additional auxiliary medications include various antihistamines (loratadine, levocetirizine, desloratadine, fexofenadine, cetirizine, and diphenhydramine), famotidine, paracetamol combination products, and methylprednisolone, which may be administered orally or intravenously as needed to manage potential adverse reactions.

Eligible participants must have biopsy-confirmed diagnosis of IgA nephropathy within the past 10 years, with an estimated glomerular filtration rate (eGFR) of at least 30 mL/min/1.73m² at screening as calculated using the 2021 chronic kidney disease epidemiology creatinine formula. Participants must demonstrate proteinuria of at least 1.0 gram per day or a urine protein-to-creatinine ratio (UPCR) of at least 0.8 g/g. All participants must be clinically stable on a maximally tolerated dose of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) for at least 12 weeks prior to screening, or be intolerant of these medications. Additional background medications such as sodium-glucose cotransporter-2 inhibitors (SGLT2is), endothelin receptor antagonists (ERAs), or mineralocorticoid receptor antagonists (MRAs) are permitted if the dose has been stable for at least 12 weeks prior to screening.

The primary endpoint is the percent change from baseline in proteinuria as measured by UPCR. Secondary endpoints include change from baseline in eGFR values, percentage of participants who progress to kidney malfunction (defined as sustained 40% reduction in eGFR, eGFR below 15 mL/min/1.73m², dialysis requirement, kidney transplantation, or death from kidney failure), percentage of participants requiring rescue therapy, and percentage of participants achieving complete response (defined as UPCR less than 0.5 g/g with at least 50% reduction and stable eGFR). Additional secondary endpoints assess the pharmacokinetic profile of felzartamab through serum concentration measurements over time, immunogenicity through detection of anti-drug antibodies (ADAs), and safety parameters including treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), vital signs, physical examination findings, laboratory abnormalities, and electrocardiogram (ECG) changes.

The study is scheduled to commence participant recruitment in August 2025, with an estimated completion date in June 2029, representing an overall trial duration of approximately four years. Participants will undergo a screening visit to assess eligibility criteria, followed by randomization and treatment initiation. The study includes regular follow-up visits to monitor efficacy parameters, safety assessments, and collection of biological samples for pharmacokinetic and immunogenicity analyses. An end-of-study visit will be conducted to perform final assessments. Participants may be withdrawn from the study early if they experience adverse events requiring discontinuation, require prohibited concomitant medications, meet criteria for rescue therapy, withdraw consent, or at the discretion of the investigator for safety concerns.

The experimental medicinal product in this clinical trial is Felzartamab (also known as MOR202), which is administered as the test product. Felzartamab is formulated as a lyophilized powder for reconstitution and is administered via intravenous administration. The active substance is felzartamab, a protein-based compound. The maximum daily dose is 1625 milligrams, with a maximum total dose of 14625 milligrams over a maximum treatment period of 20 days.

The study utilizes 0.9% Saline as a placebo comparator. The saline solution is administered via intravenous administration. No specific pharmaceutical form, active substance, or dosing information is provided for this placebo product.

Loratadine in combination with pseudoephedrine hydrochloride is used as an auxiliary medication in this trial. This combination product contains chemical active substances and is administered via the oral route. The maximum daily dose is 10 milligrams, with a maximum total dose of 90 milligrams over a treatment period of up to 20 days.

Levocetirizine serves as an auxiliary treatment and is administered orally. This chemical compound has a maximum daily dose of 2.5 milligrams and a maximum total dose of 22.5 milligrams over a maximum treatment period of 20 days.

Famotidine is utilized as an auxiliary medication administered via intravenous administration. The maximum daily dose is 20 milligrams, with a maximum total dose of 180 milligrams over a treatment period of up to 20 days.

A combination product containing buclizine hydrochloride, paracetamol, and codeine phosphate is employed as an auxiliary medication. This oral formulation has a maximum daily dose of 2950 milligrams and a maximum total dose of 2950 milligrams over the treatment period of up to 20 days.

Desloratadine is administered orally as an auxiliary treatment. The maximum daily dose is 5 milligrams, with a maximum total dose of 45 milligrams over a maximum treatment period of 20 days.

Fexofenadine serves as an auxiliary medication administered via the oral route. The maximum daily dose is 60 milligrams, with a maximum total dose of 540 milligrams over a treatment period of up to 20 days.

A combination of cetirizine dihydrochloride and pseudoephedrine hydrochloride is used as an auxiliary medication administered orally. The maximum daily dose is 10 milligrams, with a maximum total dose of 90 milligrams over a maximum treatment period of 20 days.

Diphenhydramine is employed as an auxiliary treatment administered via intravenous administration. The maximum daily dose is 50 milligrams, with a maximum total dose of 450 milligrams over a treatment period of up to 20 days.

A combination product containing methylprednisolone acetate and lidocaine hydrochloride monohydrate is utilized as an auxiliary medication. This product is administered via intravenous administration, with a maximum daily dose of 100 milligrams and a maximum total dose of 550 milligrams over a maximum treatment period of 20 days.

Efficacy will be assessed through multiple parameters designed to evaluate the therapeutic benefit of **felzartamab** in adults with **IgA nephropathy**. The primary efficacy endpoint is the percent change from baseline in **proteinuria** as measured by the **urine protein to creatinine ratio (UPCR)**. Secondary efficacy endpoints include the change from baseline in **estimated glomerular filtration rate (eGFR)** values calculated using the chronic kidney disease epidemiology creatinine equation. Additional secondary endpoints comprise the percentage of participants who progressed to kidney malfunction, defined by criteria including a reduction in eGFR of at least 40 percent sustained for at least 30 days, eGFR below 15 mL/min/1.73m² for at least 30 days, undergoing dialysis for at least 30 days, undergoing kidney transplantation, or death from kidney failure. The percentage of participants requiring rescue therapy will also be evaluated. The proportion of participants achieving **complete response** will be assessed, defined as a UPCR value based on 24-hour urine collection of less than 0.5 gram per gram, a reduction in UPCR of at least 50 percent, and a stable eGFR with a decrease from baseline of 25 percent or less. Proteinuria assessments will utilize 24-hour urine collections to determine UPCR values. Kidney function will be monitored through serial measurements of eGFR calculated using standardized formulas. The study will track progression events and the need for rescue interventions throughout the treatment period.