A Phase 3 open-label, controlled, randomised, multi-centre trial comparing imlifidase and standard-of-care with standard-of-care alone in the treatment of severe anti-GBM antibody disease (Goodpasture disease)

The primary objective of this Phase 3 trial is to demonstrate the superior effect of **imlifidase** combined with standard-of-care (SoC) compared to SoC alone on kidney function in patients with severe anti-GBM antibody disease, also known as Goodpasture disease. This objective is clinically relevant as it aims to improve renal outcomes in a condition characterized by rapid kidney damage, potentially reducing the need for dialysis or transplantation.

Secondary objectives include:

• Comparing renal function between treatment arms.
• Comparing the time to reach non-toxic levels of anti-GBM antibodies between treatment arms.
• Comparing the need for plasma exchange (PLEX) within 3 months between treatment arms.
• Comparing the need for mechanical ventilation within 3 months between treatment arms.
• Comparing the presence of anti-GBM antibodies and ANCA between treatment arms.
• Comparing longitudinal changes in health-related quality of life (HRQoL) and health status between treatment arms.
• Assessing the pharmacokinetics (PK) and pharmacodynamics (PD) of imlifidase.
• Assessing the immunogenicity profile of imlifidase.
• Assessing the safety and tolerability of imlifidase.
• Assessing long-term outcomes in terms of kidney and patient survival and recurrence of anti-GBM disease.

These secondary objectives are crucial for understanding the broader impact of imlifidase on patient health, treatment efficacy, and safety, providing comprehensive insights into its potential as a therapeutic option for Goodpasture disease.

The clinical trial involves a total of **15 participants** diagnosed with **Anti-GBM antibody disease (Goodpasture disease)**. The study population includes both male and female subjects, aged **18 years and older**, with a focus on individuals who are part of a vulnerable population. Participants were selected based on specific criteria, including an anti-GBM antibody level above a toxic threshold, presence of haematuria, and an estimated glomerular filtration rate (eGFR) of less than 20 mL/min/1.73 m². All participants are required to provide written informed consent and demonstrate the ability to comply with the study protocol. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The selection process ensures that the participants meet the necessary health status and disease-specific criteria to evaluate the effect of imlifidase and standard of care (SoC) on kidney function.

The clinical trial is designed as a **randomized**, controlled, open-label, multi-center study to evaluate the efficacy of **imlifidase** in combination with standard-of-care (SoC) compared to SoC alone in the treatment of severe **anti-GBM antibody disease** (Goodpasture disease). The primary objective is to demonstrate the superior effect of imlifidase and SoC on kidney function, as measured by estimated glomerular filtration rate (eGFR) at six months. The trial is expected to run from January 2023 to November 2026, with an estimated duration of participant involvement of up to six months.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as anti-GBM antibody levels, presence of haematuria, and eGFR below 20 mL/min/1.73 m². Following randomization, participants will receive either the investigational treatment or SoC alone. Follow-up visits will occur at regular intervals to monitor renal function, antibody levels, and other health parameters. The end-of-study visit will evaluate the primary and secondary endpoints, including renal function and the proportion of patients with functioning kidneys.

The trial includes specific conditions for early termination, such as adverse events or non-compliance with the study protocol. Participants are required to provide written informed consent and demonstrate willingness to comply with study requirements. The trial's primary endpoint is renal function as evaluated by eGFR at six months, with secondary endpoints including the proportion of patients with functioning kidneys, time to non-toxic antibody levels, and health-related quality of life assessments. The study aims to provide valuable insights into the treatment of this rare disease, with the potential to improve patient outcomes significantly.

The clinical trial involves the administration of several **experimental medications** and non-experimental treatments. The primary experimental medication is **Imlifidase**, marketed as Idefirix, which is provided as a powder for concentrate for solution for infusion. It is administered via **intravenous infusion** at a dosage of 0.50 mg/kg, with a maximum treatment period of 1 day. Imlifidase is an orphan drug designated for the treatment of severe anti-GBM antibody disease, also known as Goodpasture disease. The product is manufactured by Hansa Biopharma AB and is classified under the ATC code L04AA41.

**Loratadine** is used as an auxiliary treatment in the trial. It is an antihistamine provided in tablet form, administered orally. The maximum daily dose is 10 mg, with a total treatment period of 1 day. Loratadine is a chemical substance and is not a pediatric formulation.

**Prednisolone** is another auxiliary treatment, classified as a glucocorticoid. It is available in tablet form and administered orally. The maximum daily dose is 75 mg, with a total treatment period of 26 weeks. Prednisolone is a chemical substance and is not formulated for pediatric use.

**Cyclophosphamide** is included as an auxiliary immunosuppressive treatment. It is provided as an injection/infusion and administered intravenously. The maximum daily dose is 1 g, with a total treatment period of 26 weeks. Cyclophosphamide is a chemical substance and is not a pediatric formulation.

**Sulfamethoxazole** is used as a prophylactic antifungal treatment in the trial. It is available in tablet form and administered orally. The maximum daily dose is 1600 mg, with a total treatment period of 3 months. Sulfamethoxazole is a chemical substance and is not formulated for pediatric use.

**Trimethoprim** is also used as a prophylactic antifungal treatment. It is provided in tablet form and administered orally. The maximum daily dose is 320 mg, with a total treatment period of 3 months. Trimethoprim is a chemical substance and is not a pediatric formulation.

**Methylprednisolone** is included as an auxiliary glucocorticoid treatment. It is provided as a powder and solvent for solution for injection/infusion and administered via intravenous infusion. The maximum daily dose is 500 mg, with a total treatment period of 3 days. Methylprednisolone is a chemical substance and is not formulated for pediatric use.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints focused on evaluating kidney function and other related parameters in patients with severe anti-GBM antibody disease, also known as **Goodpasture disease**. The primary endpoint is the assessment of renal function as evaluated by estimated glomerular filtration rate (eGFR) at 6 months. Secondary endpoints include the proportion of patients with a functioning kidney at 6 months, defined as no dialysis events within 4 weeks prior to assessment, and the time to reach non-toxic levels of anti-GBM antibodies.

Additional secondary endpoints involve the evaluation of renal function by eGFR at 3 months, the proportion of patients with a functioning kidney at 3 months, and the proportion of patients experiencing end-stage renal disease (ESRD) or death due to anti-GBM disease within 6 months. Other measures include urine creatinine clearance, U-albumin levels, and U-albumin/creatinine ratio at various timepoints, as well as the number of plasmapheresis (PLEX) sessions and days on dialysis within specified periods from randomization.

Patient-reported outcomes will be assessed using the PROMIS-29 and EQ-5D-5L instruments to evaluate health-related quality of life (HRQoL) and health status from screening to 6 months. Pharmacokinetic (PK) and pharmacodynamic (PD) profiles of imlifidase, as well as anti-imlifidase antibody levels, will be monitored from the start of treatment to specified timepoints. The efficacy assessments will be conducted at designated intervals, including screening, 3 months, and 6 months, to ensure comprehensive evaluation of the treatment's impact on the disease.