SCY-635
Also known as: non-immunosuppressive cyclosporin A analog, SCY635, Scynexis cyclophilin inhibitor
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Summary
SCY-635 is an investigational, orally active cyclophilin inhibitor derived from cyclosporine A but lacking immunosuppressive activity. It is being explored as a novel antiviral agent for chronic hepatitis C virus (HCV) infection and potentially other liver diseases where cyclophilin A plays a pathogenic role.
Mechanism of Action
SCY-635 binds to the peptidyl‑prolyl isomerase domain of cyclophilin A and B, inhibiting their enzymatic activity at nanomolar concentrations while sparing calcineurin. By blocking the interaction between cyclophilin A and the HCV non‑structural protein NS5A, it disrupts a critical host‑viral complex required for viral RNA replication. In patients, the drug also appears to trigger rapid increases in endogenous interferons (type I and III) and interferon‑stimulated genes, which may augment its antiviral effect.
What the Research Shows
In vitro studies demonstrated that SCY-635 potently suppresses HCV replication and synergises with interferon‑α2b, while adding to ribavirin activity. Animal models showed oral bioavailability and drug levels exceeding the effective concentration in replicon assays. A phase‑1b dose‑escalation trial in 20 genotype‑1 HCV patients (100‑300 mg three times daily for 15 days) reported a mean 2.24‑log reduction in plasma viral load without dose‑limiting toxicities; antiviral response correlated with IL28B genotype and was accompanied by transient rises in IFN‑α, IFN‑λ1/λ3 and 2′5′‑OAS‑1. Additional pre‑clinical work confirmed that SCY‑635 disrupts CypA‑NS5A complexes across genotypes 1‑3 and can clear replicon‑containing cells, although resistance mutations in NS5A can bypass cyclophilin dependence.
Reported Benefits
Early clinical data suggest SCY‑635 can achieve substantial short‑term reductions in HCV RNA, offering a non‑immunosuppressive alternative to cyclosporine‑based regimens. Its mechanism of targeting a host factor may limit viral resistance, and the observed induction of innate interferons could enhance antiviral immunity. Pre‑clinical synergy with interferon and ribavirin points to potential combination strategies, and its oral formulation facilitates outpatient use.
Limitations of the Evidence
Evidence is limited to laboratory models, animal studies, and a small phase‑1b trial; long‑term efficacy, durability of viral suppression, and impact on clinical outcomes remain untested. Resistance can arise via NS5A mutations that render the virus cyclophilin‑independent. No data exist for other HCV genotypes, co‑infection states, or liver diseases beyond HCV. The compound has not progressed to later‑phase trials, and safety beyond the short 15‑day exposure is unknown.
Safety Considerations
The phase‑1b study reported no dose‑limiting clinical or laboratory toxicities across doses up to 900 mg per day. Compared with cyclosporine, SCY‑635 shows minimal inhibition of calcineurin and weaker suppression of IL‑2 secretion, suggesting reduced immunosuppression. In vitro metabolism studies indicated no induction of major CYP enzymes (1A2, 2B6, 3A4) and only weak interaction with P‑glycoprotein. Nonetheless, comprehensive safety profiling, including hepatic, renal, and immunologic parameters over longer periods, has not been published.
How It Is Administered
SCY‑635 is administered orally; in the phase‑1b study participants took tablets three times daily for 15 days. Pre‑clinical data confirm oral bioavailability in several species, and drug concentrations in blood and liver exceeded the in‑vitro effective dose. Formulation details beyond tablet dosing are not described in the available literature.
Routes of Administration
Goals & Uses
- Combination antiviral therapyAntiviralModerate
- Pan-genotypic HCV coverageAntiviralModerate
- Avoidance of immunosuppressionSafety ProfileModerate
- HCV antiviral activityAntiviralModerate
Contraindications
- Hypersensitivity to cyclosporine or cyclosporin analogsAllergyHigh
- Severe renal impairmentOrganModerateKidney function concerns
- PregnancyPopulationHighPotential fetal risk or insufficient safety data
Adverse Effects
- HeadacheNeurologicCommonPain in the head or upper neck
- Gastrointestinal disturbances (nausea, diarrhea)GastrointestinalCommon
- FatigueGeneralCommonLow energy or tiredness
- Elevated serum creatinineRenal / LaboratoryUncommon
- HyperbilirubinemiaHepaticUncommon
Drug Interactions
- Pegylated interferon alfaLow
- CYP3A4 inducers (e.g., rifampin, carbamazepine)Moderate
- Immunosuppressants (e.g., tacrolimus, cyclosporine A)High
- CYP3A4 inhibitors (e.g., ketoconazole, ritonavir)High
Population Constraints
- Pediatric patientsAgeRelative
- Patients with hepatic impairmentOrgan FunctionRelative
- Organ transplant recipients on immunosuppressionComorbidityRelative
Regulatory Status
- European UnionInvestigationalNo marketing authorization application submitted; investigational status only
- United StatesInvestigationalCompleted Phase II trials for chronic HCV; no NDA filed; development discontinued
- United KingdomInvestigationalNo regulatory submission; research/investigational use only
SCY-635 completed Phase II clinical trials for HCV but was not advanced to Phase III or submitted for regulatory approval. No approved status in any jurisdiction. Investigational use only.
Evidence & Sources
- Journal ArticleLowHopkins S, et al.2010-01-01T00:00:00.000000Z
- Journal ArticleModerateNaoumov NV2014-01-01T00:00:00.000000Z
- Journal ArticleLowTomillero A, Moral MA2010-01-01T00:00:00.000000Z
- Journal ArticleLowHopkins S, et al.2012-01-01T00:00:00.000000Z
- Journal ArticleModerateHopkins S, et al.2012-01-01T00:00:00.000000Z
- Journal ArticleModerateLee J2013-01-01T00:00:00.000000Z
Frequently Asked Questions
What disease is SCY‑635 being studied for?
The compound is under investigation as an antiviral agent for chronic hepatitis C virus infection, where it targets the host protein cyclophilin A to inhibit viral replication.
Is SCY‑635 an immunosuppressant like cyclosporine?
No. Although derived from cyclosporine A, SCY‑635 lacks detectable calcineurin inhibition and shows only weak suppression of interleukin‑2 secretion, making it non‑immunosuppressive in the reported studies.
How effective was SCY‑635 in human trials?
In a phase‑1b trial of 20 patients, a 15‑day course reduced plasma HCV RNA by an average of 2.24 log₁₀ units at the highest dose, with no dose‑limiting toxicities observed.
Can SCY‑635 be used together with other hepatitis C drugs?
In vitro experiments showed synergistic antiviral activity when combined with interferon‑α2b and additive effects with ribavirin, suggesting potential for combination therapy, though clinical combination data are not yet available.
What are the known safety concerns for SCY‑635?
Short‑term exposure up to 900 mg per day was well tolerated, and the drug does not induce major CYP enzymes or strongly interact with P‑glycoprotein. However, long‑term safety, rare adverse events, and effects in broader patient populations have not been established.
What is SCY-635?
SCY-635 is an investigational, orally active cyclophilin inhibitor derived from cyclosporine A but lacking immunosuppressive activity. It is being explored as a novel antiviral agent for chronic hepatitis C virus (HCV) infection and potentially other liver diseases where cyclophilin A plays a pathogenic role.
What is SCY-635 used for?
SCY-635 is educationally associated with: Combination antiviral therapy, Pan-genotypic HCV coverage, Avoidance of immunosuppression, HCV antiviral activity. Educational only — not medical advice.
How is SCY-635 administered?
Recorded routes of administration: Oral.
What are the potential side effects of SCY-635?
Reported adverse effects include: Headache, Gastrointestinal disturbances (nausea, diarrhea), Fatigue, Elevated serum creatinine, Hyperbilirubinemia. This list is not exhaustive — consult a qualified clinician.
Who should avoid SCY-635?
Recorded contraindications: Hypersensitivity to cyclosporine or cyclosporin analogs, Severe renal impairment, Pregnancy. Consult a qualified clinician before use.