Biotech Values

[oc631]

ENTA—One thing the EP Vantage article didn’t mention

Concerning ENTA. It looks as if NVS hasn't given up on the Cyclophilin Inhibitor Alisporivir which has been released from clinical hold. This abstract suggests NVS may be moving forward with the HTA/EDP-239 combination in GT2/GT3 patients.




Abstract:
TITLE: The Combination of Alisporivir with an NS5A Inhibitor Provides Additive to Synergistic Antiviral Activity, no Cross-Resistance and a High Barrier to HCV Resistance
AUTHORS (FIRST NAME, LAST NAME): Udayan Chatterji1, Kelly A. Wong2, Weidong Zhong2, Clifford Brass3, Nikolai V. Naoumov4, Philippe Gallay1
INSTITUTIONS (ALL): 1. The Scripps Research Institute, La Jolla, CA, United States.
2. Novartis Institutes for BioMedical Research, Emeryville, CA, United States.
3. Novartis Pharmaceuticals Corporation, East Hanover, NJ, United States.
4. Novartis Pharma AG, Basel, Switzerland.
ABSTRACT BODY: Two principal groups of HCV antivirals exist: direct-acting antivirals (DAAs) and host-targeting antivirals (HTAs). DAAs target viral proteins e.g. NS3 protease, NS5B polymerase or NS5A, while HTAs target host proteins critical for HCV replication. Both groups of antivirals were shown to profoundly reduce HCV replication in vitro and in patients with hepatitis C. In this study, we investigated whether particular DAAs exhibit additive, synergistic or antagonistic effects when combined with an HTA - Alisporivir (ALV), which targets cyclophilin A (CypA). We used different HCV genotypes established as stable luciferase reporter replicon cell lines to test the effect of ALV in combination with different classes of DAAs: NS3, NS5A and NS5B inhibitors. Compounds were tested at concentrations near EC50 values calculated in reporter cell lines specific to each genotype. Cell viability and reporter assays were carried out in five replicates for each drug combination and the normalized data were used to analyze the synergy between different combinations using MacSynergyII. In contrast to the DAAs tested, ALV was found to exert potent antiviral activity against all HCV genotypes tested (EC50 of 8, 16, 17 and 20 nM for genotypes 1a, 1b, 2a and 3a, respectively). The combinations of ALV with DAAs exerted mostly additive effects against genotypes 1a and 1b (synergy values of ~ 0). Importantly, combining ALV with certain DAA classes exerted synergistic antiviral effect on genotypes 2a and 3a. The most profound synergistic effect was observed with the combination of ALV with NS5A inhibitors (NS5Ai) (synergy values of 15 to 68). This is consistent with the finding that ALV blocks the contact between CypA and domain II of NS5A, whereas NS5Ai target domain I of NS5A. Thus, the synergistic effects of the combination of ALV and NS5Ai may arise from the mechanism of action of these two classes of antivirals targeting distinct loci of NS5A. Importantly, we did not observe any cross-resistance between ALV and NS5Ai. Because NS5Ai and ALV exhibit a low and a high barrier to HCV resistance, respectively, we examined HCV resistance to a combination of the drugs. No resistant mutants were detected to the combination of ALV and NS5Ai after extensive in vitro drug selection (>6 months), whereas NS5Ai-resistant and ALV-resistant mutants emerged after two weeks and two months, respectively. In conclusion, these results suggest that the combination of the HTA Alisporivir with NS5A inhibitors represents an attractive strategy, and is potentially an effective IFN-free combination regimen for treatment of HCV patients.