Alisporivir
Also known as: Alisporivir, ALV, Cyclophilin inhibitor Debio 025, DEB025, Debio 025, Debio‑025, SCY‑635
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Summary
Alisporivir (Debio‑025) is an investigational oral cyclic peptide that inhibits the host protein cyclophilin A. It has been developed primarily as a host‑targeting antiviral for chronic hepatitis C virus (HCV) infection, with additional pre‑clinical studies suggesting activity against other viruses such as SARS‑CoV‑2.
Mechanism of Action
Alisporivir binds to cyclophilin A, a peptidyl‑prolyl cis/trans isomerase abundant in hepatocytes. By blocking cyclophilin’s enzymatic activity, the drug prevents the proper folding of viral proteins that rely on this host factor, thereby halting HCV RNA replication. The same cyclophilin inhibition also interferes with replication cycles of several other viruses in vitro.
What the Research Shows
Early‑phase clinical work showed that alisporivir reduced HCV RNA levels in monotherapy and when combined with pegylated interferon‑α or ribavirin, achieving rapid viral load declines across genotypes 1‑3. Phase I testing in HIV‑1 patients revealed minimal antiviral effect. Pre‑clinical models explored its use in muscular dystrophy, myocardial infarction, and brain disorders. In vitro assays demonstrated inhibition of SARS‑CoV‑2 replication, though no clinical data exist. While phase II trials reported potent antiviral activity and a favorable pharmacokinetic profile, the program was halted after reports of serious pancreatitis, limiting further development.
Reported Benefits
Alisporivir’s host‑targeting mechanism provides pangenotypic activity against HCV and a high barrier to resistance, with no cross‑resistance to direct‑acting antivirals. Clinical studies reported dramatic reductions in viral load, even in patients previously unresponsive to interferon‑based regimens, and additive effects when paired with other antivirals. Early safety data indicated tolerability comparable to standard pegylated interferon‑α/ribavirin therapy, aside from laboratory hyperbilirubinemia.
Limitations of the Evidence
Development was stopped after three cases of pancreatitis, including one fatality, raising significant safety concerns. Efficacy data are limited to phase I/II trials; no large‑scale phase III results are available. The drug showed little impact on HIV‑1 and has only in‑vitro evidence for SARS‑CoV‑2. Consequently, its clinical role remains unestablished, and further investment is uncertain.
Safety Considerations
Initial trials described alisporivir as generally well tolerated, with the most common laboratory abnormality being reversible hyperbilirubinemia due to transporter inhibition rather than liver injury. However, serious adverse events—particularly pancreatitis (three reported cases, one lethal)—prompted the FDA to halt studies. Ongoing safety assessment would need to monitor pancreatic enzymes, bilirubin, and potential drug‑drug interactions.
How It Is Administered
Alisporivir is administered orally as an investigational formulation. Dosing regimens have varied across early trials, but specific dose amounts and schedules are not established for clinical use. The oral route facilitates outpatient administration compared with injectable antivirals.
Routes of Administration
Goals & Uses
- Duchenne muscular dystrophyMuscle DiseaseLow
- Treatment of chronic hepatitis C infectionAntiviral / Infectious DiseaseModerate
- Hepatitis C virus infectionAntiviralModerate
- Prevention of ischemia-reperfusion injuryCardioprotection / CytoprotectionLow
- Combination antiviral therapy (with pegIFN/ribavirin or DAAs)Antiviral Combination RegimenModerate
- Treatment of mitochondrial diseases (e.g., MELAS, Sengers syndrome)Rare / Orphan DiseaseLow
- Broad‑spectrum antiviral therapyAntiviralModerate
Contraindications
- Hypersensitivity to cyclosporine analoguesAllergy / ImmunologyHigh
- Severe hepatic impairmentOrganHighLiver function concerns
- Known hypersensitivity to cyclosporine derivativesAllergyModerate
- PregnancyPopulationModeratePotential fetal risk or insufficient safety data
- History of pancreatitisGastrointestinalHigh
Adverse Effects
- Elevated transaminases (ALT/AST)HepaticCommon
- HeadacheNeurologicCommonPain in the head or upper neck
- Elevated liver enzymes (ALT/AST)HepaticUncommon
- NauseaGastrointestinalCommonFeeling of sickness or urge to vomit
- FatigueGeneralCommonLow energy or tiredness
- Acute pancreatitisGastrointestinalUncommon
- HyperbilirubinemiaHepaticUncommon
Drug Interactions
- Strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir)High
- Cyclosporine AModerate
- P‑gp inhibitors (e.g., verapamil)Moderate
- Strong CYP3A4 inducers (e.g., rifampicin, carbamazepine)Moderate
- P-glycoprotein substratesModerate
Population Constraints
- PregnancyReproductive SafetyRelative
- Renal impairmentOrgan ImpairmentRelative
- Pediatric patientsAgeRelative
- Patients with prior pancreatitis or risk factors for pancreatitisGastrointestinalAbsolute
- Elderly (>75 y)AgeRelative
Regulatory Status
- European UnionInvestigationalClinical trial authorization only; no EMA marketing authorization.
- United StatesInvestigationalInvestigational New Drug (IND) status; no FDA approval.
- United KingdomInvestigationalMHRA clinical trial permission; not marketed.
Development discontinued after phase II/III studies because of liver safety signals; not approved in any jurisdiction.
Evidence & Sources
- Journal ArticleModerateWatashi K2010-01-01T00:00:00.000000Z
- Journal ArticleModerateGallay PA, Lin K2013-01-01T00:00:00.000000Z
- Journal ArticleModerateStanciu C, et al.2019-01-01T00:00:00.000000Z
- Journal ArticleModerateYang PL, et al.2011-01-01T00:00:00.000000Z
- Journal ArticleModeratePoulsen NN, et al.2020-01-01T00:00:00.000000Z
- Journal ArticleModerateFrausto SD, Lee E, Tang H2013-01-01T00:00:00.000000Z
Frequently Asked Questions
What makes alisporivir different from other hepatitis C drugs?
Unlike direct‑acting antivirals that target viral proteins, alisporivir blocks the host enzyme cyclophilin A, giving it activity against all HCV genotypes and a high barrier to viral resistance.
Has alisporivir been approved for any disease?
No. Alisporivir remains an investigational compound; clinical development was discontinued after safety concerns, and it has not received regulatory approval for any indication.
Can alisporivir be used to treat COVID‑19?
Only laboratory studies have shown that alisporivir can inhibit SARS‑CoV‑2 replication in cell culture. There is no clinical evidence that it prevents or treats COVID‑19 in patients.
What are the main safety concerns with alisporivir?
Early trials reported reversible hyperbilirubinemia, but the most serious issue was pancreatitis, observed in three patients (one fatal), which led to the termination of its development.
Is alisporivir taken as a pill or injection?
The compound is designed for oral administration; all clinical studies to date have used an oral formulation.
What is Alisporivir?
Alisporivir (Debio‑025) is an investigational oral cyclic peptide that inhibits the host protein cyclophilin A. It has been developed primarily as a host‑targeting antiviral for chronic hepatitis C virus (HCV) infection, with additional pre‑clinical studies suggesting activity against other viruses such as SARS‑CoV‑2.
What is Alisporivir used for?
Alisporivir is educationally associated with: Duchenne muscular dystrophy, Treatment of chronic hepatitis C infection, Hepatitis C virus infection, Prevention of ischemia-reperfusion injury, Combination antiviral therapy (with pegIFN/ribavirin or DAAs), Treatment of mitochondrial diseases (e.g., MELAS, Sengers syndrome), Broad‑spectrum antiviral therapy. Educational only — not medical advice.
How is Alisporivir administered?
Recorded routes of administration: Oral.
What are the potential side effects of Alisporivir?
Reported adverse effects include: Elevated transaminases (ALT/AST), Headache, Elevated liver enzymes (ALT/AST), Nausea, Fatigue, Acute pancreatitis, Hyperbilirubinemia. This list is not exhaustive — consult a qualified clinician.
Who should avoid Alisporivir?
Recorded contraindications: Hypersensitivity to cyclosporine analogues, Severe hepatic impairment, Known hypersensitivity to cyclosporine derivatives, Pregnancy, History of pancreatitis. Consult a qualified clinician before use.