Is Alisporivir (Debio 025) effective in treating Alport syndrome?

Alisporivir is Not Effective for Treating Alport Syndrome

There is currently no evidence supporting the use of Alisporivir (Debio 025) for treating Alport syndrome, and it should not be used for this condition.

Understanding Alport Syndrome

Alport syndrome is a hereditary glomerular disease characterized by:

• Progressive hematuric nephritis leading to end-stage kidney disease (ESKD)
• Sensorineural hearing loss
• Genetic mutations in type IV collagen genes (COL4A3, COL4A4, COL4A5)
• Different inheritance patterns: X-linked, autosomal recessive, autosomal dominant, or digenic

Alport syndrome is recognized as one of the syndromes associated with hearing loss and progressive kidney disease 1. It is characterized by defective glomerular basement membrane structure due to mutations in type IV collagen genes, resulting in proteinuria, hematuria, and progressive kidney failure.

Current Evidence-Based Treatment Options

First-Line Therapy: RAAS Blockers

• Renin-angiotensin-aldosterone system (RAAS) blockers are the current standard of care for Alport syndrome
• Recent meta-analysis shows RAAS blockers significantly reduce progression to ESKD (HR 0.33,95% CI 0.24-0.45) 2
• Benefits observed across all genetic types:
  • Male X-linked AS (HR 0.32,95% CI 0.22-0.48)
  • Autosomal recessive AS (HR 0.25,95% CI 0.10-0.62)
  • Female X-linked and autosomal dominant AS (HR 0.40,95% CI 0.21-0.75)
• Early initiation of RAAS blockade is crucial for optimal outcomes

Other Treatment Approaches Under Investigation

1. Cyclosporine:

   • May reduce proteinuria but has significant nephrotoxicity
   • Long-term use is not recommended due to adverse effects 3
   • Control renal biopsies revealed significant lesions of cyclosporin nephrotoxicity

2. SGLT2 inhibitors:

   • Potential benefit based on DAPA-CKD trial
   • Limited data specifically for Alport syndrome patients 4

3. Novel therapies under investigation:

   • Bardoxolone methyl (NRf2 activator)
   • Lademirsen (anti-miRNA-21)
   • Sparsentan (dual endothelin type A and angiotensin 1 receptor inhibitor)
   • Atrasentan (selective ETAR inhibitor)
   • Lipid-modifying agents
   • Hydroxychloroquine 5, 4

Alisporivir and Alport Syndrome

Alisporivir (Debio 025) is a non-immunosuppressive cyclophilin inhibitor that was primarily developed for hepatitis C treatment. There is no evidence in the provided literature or current guidelines suggesting any role for Alisporivir in treating Alport syndrome:

• None of the guidelines mention Alisporivir for Alport syndrome management
• No clinical trials have evaluated Alisporivir specifically for Alport syndrome
• The mechanism of action of Alisporivir does not directly address the underlying pathophysiology of Alport syndrome (defective type IV collagen)

Clinical Approach to Alport Syndrome Management

1. Early diagnosis:

   • Kidney biopsy is the gold standard for diagnostic evaluation 1
   • Genetic testing for mutations in COL4A3, COL4A4, and COL4A5 genes

2. Treatment initiation:

   • Start RAAS blockers at early stages of disease
   • Monitor for proteinuria and kidney function

3. Regular monitoring:

   • Kidney function (eGFR)
   • Proteinuria
   • Hearing assessment 1

4. Consider referral for kidney transplantation when approaching end-stage kidney disease

Conclusion

Based on current evidence, Alisporivir (Debio 025) has no established role in treating Alport syndrome. The standard of care remains RAAS blockade, which has demonstrated efficacy in slowing disease progression. Future therapies targeting the underlying pathophysiology of Alport syndrome are under investigation, but none have yet replaced RAAS blockers as first-line therapy.