What is the role of Alisprovir in treating viral infections?

Alisprovir in Treating Viral Infections

Alisprovir is a cyclophilin inhibitor with demonstrated efficacy against hepatitis C virus (HCV) and potential activity against coronaviruses, including SARS-CoV-2, making it a promising antiviral agent for specific viral infections where other treatment options are limited or ineffective. 1

Mechanism of Action

Alisprovir (previously known as Debio 025) works through a host-targeting mechanism rather than directly targeting viral proteins:

• Neutralizes the peptidyl-prolyl isomerase activity of cyclophilin A, a host protein essential for viral replication 1
• This unique mechanism provides:
  • Pangenotypic activity against HCV
  • High barrier to viral resistance development
  • No cross-resistance with direct-acting antivirals 1

Clinical Applications in HCV Infection

Alisprovir has been extensively studied for hepatitis C treatment:

• Most advanced in clinical development for HCV infection (reached Phase 3 trials) 1
• Demonstrated efficacy in both treatment-naïve and treatment-experienced patients 1, 2
• Particularly effective against genotypes 1,2, and 3 2, 3
• Combination therapy results:
  • With peginterferon and ribavirin: 69% SVR12 vs. 53% in control group 2
  • Highest SVR12 (90%) achieved with alisprovir 400mg twice daily plus PR for >24 weeks 2
  • Alisprovir plus ribavirin as interferon-free therapy showed 92% SVR24 in patients with rapid virological response 3

Potential Role in COVID-19

Recent research suggests alisprovir may have application in COVID-19 treatment:

• Coronaviruses, including SARS-CoV and MERS-CoV, show strong cyclophilin dependency in their life cycles 4
• Preclinical data demonstrates both antiviral and cytoprotective properties against coronaviruses, including SARS-CoV-2 4
• Proposed as a potential therapeutic option for patients with or at risk of severe COVID-19 4

Safety Profile and Adverse Effects

Alisprovir has a generally favorable safety profile with some important considerations:

• Common adverse events: anemia, thrombocytopenia, hyperbilirubinemia, and hypertension 2
• Serious concern: pancreatitis (led to FDA clinical hold in 2012)
  • Reported in approximately 0.6% of patients in clinical trials 2
  • One fatal case reported, which contributed to interruption of development 5
• Hyperbilirubinemia is related to transporter inhibition rather than liver toxicity 1
• Generally better tolerated than interferon-containing regimens 3

Current Status and Future Directions

Despite promising results, alisprovir's development status is complicated:

• Development for HCV was halted after FDA clinical hold due to pancreatitis concerns 5
• With current highly effective direct-acting antivirals for HCV, its role in HCV treatment is uncertain 5
• Potential applications remain for:
  • Patients with multi-resistant HCV infections 5
  • Difficult-to-treat populations (prior non-responders, cirrhotic patients) 1
  • COVID-19 and other coronavirus infections 4

Clinical Considerations and Pitfalls

When considering alisprovir use:

• Monitor for signs of pancreatitis (abdominal pain, nausea, vomiting)
• Be aware of hyperbilirubinemia, which may occur but is not indicative of liver damage
• Consider alisprovir's high barrier to resistance in patients with treatment-resistant viral infections
• For HCV, combination therapy (particularly with ribavirin) appears more effective than monotherapy 3

Alisprovir represents a unique approach to antiviral therapy through host-targeting rather than direct viral inhibition, offering potential advantages in certain clinical scenarios where conventional antivirals may be ineffective or resistance has developed.