Background:

Childhood Nephrotic Syndrome

• onset typically 2-7yo
• affects boys > girls 2:1
• BP and kidney function typically normal,
• BUT up to 15-20% have haematuria/abnormal kidney function
• Is a syndrome, not a disease diagnosis
• Underlying diseases include:
  • Minimal Change Disease (MCD)
  • Focal Segmental Glomerulosclerosis (FSGS)
  • Other (IgA nephropathy/vasculitis, C3 glomerulopathy, lupus nephritis)

Minimal Change Disease (MCD)

• Affects 1-3 per 100,000 children in USA
• Usually responsive to treatment, but >70% have relapses
• Relapses usually become milder and less frequent with time, and often stop in adolescence
• Children are more likely to experience relapses into adulthood if disease onset at <6yo

Focal Segmental Glomerulosclerosis (FSGS)

• Represents 15-20% of childhood nephrotic syndrome
• Onset usually older than MCD (50% are >6yo at onset)
• More common in African-American & Hispanic populations
• Low rate of response to currently available therapies
• End-stage kidney disease develops in >25-50%

C3 glomerulopathy

• Characterized by complement dysregulation
• In most patients, disease is driven by acquired factors: autoantibodies targeting complement proteins and complexes. Variants in complement-related genes are less frequently observed.
• Diagnosis is made on kidney biopsy (no diagnostic biomarkers)
• Post-infectious glomerulonephritis cannot be differentiated from C3 glomerulopathy by biopsy alone: this can confound early diagnosis/treatment.
• 50% approach end-stage kidney disease in 10 years.
• After transplantation, clinical recurrence is seen in 50% and histological recurrence in 90%.
• Clinical trials currently in progress with agents targeting the alternative pathway of complement, including inhibitors of MASP, Factor D, Factor B and C3, and the C5a receptor blocker, avacopan. Of these, only the avacopan study is recruiting children (from age 12yo) https://clinicaltrials.gov/ct2/show/NCT03301467

Practical Considerations in Pediatric GN Clinical Trials

• Limited trials in children can mean:
  • children do not receive potentially beneficial medications because these agents have not been approved for pediatric use
  • children receive medications based on evidence from adult studies and limited anecdotal pediatric clinical experience (off-label use)
• Practical issues in administering clinical trials:
  • Is the protocol feasible?
  • Do we have enough eligible patients?
  • Are there any competing studies?
  • Managing referrals from other centres (patient and family unfamiliar with treating team, travel and accommodation logistics)
  • Coordinating visit schedules with school/family commitments
  • Education about study procedures (e.g. accurate urine specimen collection)
• Identifying active clinical trials:
  • clinicaltrials.gov – U.S. National Library of Medicine database of clinical studies worldwide
  • kidneyhealthgateway.com – user-friendly portal created by NephCure to help patients with kidney disease identify clinical trials and connect directly with research teams. A physician portal is in development.

Regulatory Considerations in Pediatric GN Clinical Trials

• Regulations in USA and Europe require that sponsors developing a new medication (including new formulation, new route of administration, new indication) submit a plan for investigation in the pediatric population
• Waiver or deferral of pediatric studies is common (e.g. until after evaluation of adult safety data)
• ‘Orphan’ indications (conditions affecting <200,000 individuals – e.g. pediatric GN diseases) are excluded from the mandate
• Companies are incentivized to conduct pediatric studies by the provision of a period of market exclusivity
• A comprehensive pediatric plan established early in drug development not only benefits pediatric patients but assures no delay in market entry

Selected Resources:

https://www.ncbi.nlm.nih.gov/pubmed/26656320

https://www.ncbi.nlm.nih.gov/pubmed/30692664

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6224619/

kidneyhealthgateway.com

clinicaltrials.gov