Profile of alisporivir and its potential in the treatment of hepatitis C

Figures & data

Figure 1 Structure of alisporivir.

Notes: The chemical name of alisporivir is cyclo[L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl- (2S,3R,4R,6E)-3-hydroxy-4-methyl-2-(methylamino)-6-octenoyl-(2S)-2-aminobutanoyl- N-methyl-D-alanyl-N-ethyl-L-valyl-L-valyl-N-methyl-L-leucyl]. The molecular formula of alisporivir is C₆₃H₁₁₃ N₁₁O₁₂ and its molecular weight is 1216.6.

Table 1 Summary of results of the VITAL-1 and FUNDAMENTAL studies

Study	Treatment	Results
VITAL-1	Arm 1: Alisporivir 1,000 mg qd^Table Footnotea–Table Footnotec Arm 2: Alisporivir 600 mg qd^Table Footnotea–Table Footnotec plus ribavirin Arm 3: Alisporivir 800 mg qd^Table Footnotea–Table Footnotec plus delayed addition of IFN and ribavirin Arm 4: Alisporivir 600 mg qd ^a plus IFN and ribavirin	Alisporivir exposure, low baseline viral load and ribavirin dose were the most important parameters to predict high RVR. The safety profile of the IFN-free alisporivir treatment was markedly superior to that of IFN-containing regimens. The final results of the study demonstrated that alisporivir combined with ribavirin achieves high rates of sustained HCV clearance (SVR24) as IFN-free or IFN-add-on regimen in treatment-naïve genotype 2- or 3-infected patients with early HCV clearance, with low viral breakthrough or post-treatment relapse. All alisporivir treatment groups maintained higher virological response rates compared to IFN and ribavirin, and patients, who received the 400 mg bid dose, exhibited the highest viral drop. Alisporivir improved VR24 in relapsers compared to IFN and ribavirin. The 400 mg bid alisporivir dose improved VR24 in nonresponders compared to IFN and ribavirin. The 400 mg bid dose improved VR24 in the most difficult-to-treat null responders compared to IFN and ribavirin. The benefit of alisporivir was observed in all groups independently of the cirrhosis status or the IL28 allele. Viral breakthroughs were higher in nonresponders compared to relapsers. The 400 mg bid of alisporivir had the lowest viral breakthrough rate in all patient populations, which correlated with the higher Ctrough level of the compound it provided. Serious AEs were more frequent in alisporivir-treated patients compared to IFN and ribavirin-treated patients, with the greatest incidence in 400 mg bid dose-treated patients. The most frequent clinical and laboratory AEs were neutropenia, anemia, hyperbilirunemia and thrombocytopenia. Hyperbilirunemia was transient and reversible and not associated with liver toxicity.
FUNDAMENTAL	Arm 1: Alisporivir 600 mg qd ^d Arm 2: Alisporivir 800 mg qd ^d Arm 3: Alisporivir 400 mg bid Arm 4: Placebo qd or bid

Notes:

a All patients received 7 days of alisporivir 600 mg bid. On day 8 patients initiated their randomized dose of alisporivir;

b patients exhibiting RVR (<25 IU/mL) received their originally randomized regimen throughout the remainder of the 24-week treatment period;

c patients with viral load ≥ 25 lU/mL at week 4 switched treatment at week 6 to triple therapy containing alisporivir 600 mg qd plus IFN and ribavirin for the remaining 18 weeks;

d patients in arms 1 and 2 received 7 days of loading dose treatment with alisporivir 600 mg bid. On day 8 patients initiated treatment with their randomized dose of alisporivir.

Abbreviations: mg, milligram; qd, once daily; bid, twice daily; IFN, interferon; RVR, rapid virologic response; HCV, hepatitis C virus; SVR₂₄, sustained virologic response after 24 weeks; VR₂₄, virologic response after 24 weeks; IL28, interleukin 28; AEs, adverse events; IU/mL, international units/milliliter.

Figure 2 Model for the mechanism of action of alisporivir.