A randomized, double-blind, placebo-controlled, parallel group Phase 2a study with an extension phase to evaluate the efficacy and safety of BAY 3401016 in participants aged 18 to 45 with Alport syndrome

Alport Syndrome is a genetic disorder causing progressive kidney disease, hearing loss, and eye abnormalities due to mutations in the COL4A3, COL4A4, or COL4A5 genes. Alport Syndrome can be inherited in X-linked, autosomal recessive, or autosomal dominant patterns, with X-linked and autosomal recessive forms typically being more severe. Current treatments mainly manage symptoms using Angiotensin-Converting Enzyme (ACE) inhibitors and Angiotensin Receptor Blockers (ARBs) to reduce proteinuria and protect kidney function. Sema3A, a soluble protein in the Semaphorin family, is expressed in the kidneys and regulates the actin cytoskeleton. In Alport Syndrome, COL4 mutations lead to stress in podocytes, disrupting cytoskeletal dynamics and causing hematuria, albuminuria, and renal fibrosis Recombinant Sema3A has been shown to decrease slit-diaphragm protein interactions and induce podocyte apoptosis, while its inhibition improves albuminuria and podocyte health. Elevated urinary Sema3A levels correlate with kidney disease severity. Overall, inhibiting Sema3A could provide a novel therapeutic approach for Alport Syndrome, distinct from existing Renin-Angiotensin-Aldosterone System (RAAS) targeting therapies. BAY 3401016 is a humanized monoclonal antibody targeting Sema3A, developed for the treatment of Alport Syndrome. Study 22419 ASSESS study is a randomized, double-blind, placebo-controlled and a parallel group Phase 2a study with an extension phase to evaluate the efficacy and safety of BAY 3401016 in participants aged 18 to 45 years with Alport syndrome. The aim of this Phase 2a study is to explore if BAY 3401016 can reduce the decline of kidney function in participants with Alport syndrome who are at risk of fast disease progression. The study will also investigate the safety of repeat dose administration of BAY 3401016 in this population. Patients with fast progressing Alport Syndrome, characterized by rapid deterioration of kidney function, are at high risk of developing End Stage Renal Disease (ESRD) in early adulthood despite treatment with RAAS inhibitors as current standard of care. BAY 3401016 shows promise in stabilizing glomerular basement membrane function by decreasing free Sema3A, thus potentially slowing the progression to ESRD. The aim of this Phase 2a study is to explore if BAY 3401016 can reduce the decline of kidney function in a group of Alport Syndrome participants who are at risk of fast disease progression. The study will also investigate the pharmacokinetics (PK) and safety of repeat dose administration of BAY 3401016 in this population. The Phase 2a study is subdivided into 2 parts, Part A and Part B. The objective of Part A is to evaluate the effect on kidney function and safety of repeated doses of BAY 3401016 in participants with AS. Participants will be randomized 1:1 in a double-blind fashion to active treatment with repeated doses of BAY 3401016 or to placebo. Placebo control and double blinding are used to control for observer and subject bias, and randomization to control for assignment bias. The aim of Part B is to assess the long-term safety and PK of BAY 3401016. An open-label design with 24 weeks of treatment and without a control arm is considered adequate for these objectives.