Comprehensive Pharmaceutical Asset Profile: Alisporivir (DB12139)

Executive Summary

Alisporivir (DB12139) is an investigational, orally administered small molecule that represents a pioneering effort in the field of host-targeting antiviral (HTA) therapy. A semi-synthetic derivative of cyclosporine A, Alisporivir was specifically engineered to inhibit the host protein cyclophilin A (CypA) without exerting the immunosuppressive effects of its parent compound. Its primary mechanism of action involves neutralizing the peptidyl-prolyl isomerase activity of CypA, thereby disrupting the formation of the Hepatitis C Virus (HCV) replication complex. This unique host-centric mechanism conferred several highly desirable properties, including potent, pangenotypic activity and a remarkably high barrier to the development of viral resistance, positioning it as a promising candidate for HCV treatment.

Extensive clinical development, encompassing over 2,000 patients, demonstrated significant efficacy, particularly when combined with the then-standard-of-care, pegylated interferon and ribavirin (PEG/RBV). In pivotal trials, Alisporivir-containing regimens consistently produced superior sustained virologic response (SVR) rates compared to PEG/RBV alone. However, the program's trajectory was irrevocably altered in 2012 by a partial clinical hold from the U.S. Food and Drug Administration (FDA). This regulatory action was prompted by a critical safety signal—a cluster of acute pancreatitis cases, including one fatality, observed exclusively in patients receiving Alisporivir in combination with interferon-based therapy.