BARCELONA — Combination therapy with ABT-493, a novel NS3/4A protease inhibitor, and ABT-530, a pangenotypic NS5A inhibitor, produced sustained virologic response rates around 90% in a cohort of treatment-experienced patients, including those with resistance-associated variants, according to findings presented at the International Liver Congress.
Fred Poordad, MD, of The Texas Liver Institute and University of Texas Health Science Center in San Antonio, and colleagues, aimed to assess the efficacy and safety of ABT-493 and ABT-530 (AbbVie) in a cohort of genotype 1 patients without cirrhosis who previously failed therapy with an NS3 protease inhibitor and/or an NS5A-inhibitor-containing regimen with or without Sovaldi (sofosbuvir, Gilead).
“We know that treatment failure is associated with RAVs,” Poordad said. “We also know that NS5A RAVs can persist for more than 2 years.”
The multicenter, open-label, phase-2 trial included six patients treated with 200 mg ABT-493 and 80 mg ABT-530; 22 patients treated with 300 mg ABT-493, 120 mg ABT-530 and 800 mg ribavirin; and 22 patients treated with those same doses of ABT-493 and ABT-530 without ribavirin. Poordad noted that ABT-530 retains antiviral activity against common NS5A variants, including those at Q30E, L31M/V, H58D and Y93H/N.
Half of the cohort failed on an NS5A drug and 84% had failed on a protease inhibitor. NS3 or NS5A RAVs were found in five of six patients in the lower dose arm, 19 of 22 patients in the higher dose with ribavirin arm and 17 of 22 patients in the higher dose, non-ribavirin arm. Seven patients in the second arm and nine patients in the third arm had both RAVs.
Intention-to-treat analysis results indicated 100% SVR12 in the low-dose arm, 91% SVR12 in the high-dose with ribavirin arm and 86% SVR12 in the high dose without ribavirin arm.
Three patients were lost to follow-up. There were two virologic failures. One of those patients was a treatment breakthrough who had been treated with Viekira Pak (ombitasvir/paritaprevir/dasabuvir, AbbVie) plus ribavirin and had baseline Y56H, D168A/T, M28V and Q30L/R variants. The other patient, a relapse, had previously been treated with Daklinza (daclatasvir, Bristol Myers Squibb) and Incivek (telaprevir, Vertex) plus pegylated-interferon and ribavirin. This patient had no NS3 RAVs and NS5A RAVs in L31M and H58D.
SVR12 was 100% in patients with no baseline RAVs and in those with only NS3 RAVs; 90% in those with only NS5A RAVs; and 94% in those with both NS3 and NS5A RAVs. Additionally, SVR12 was 92% in patients with two or more RAVs.
“Importantly, 10 patients had the Y93 variant at baseline, and all of those patients achieved SVR,” Poordad said. “Also, all 17 patients who had been treated with a sofosbuvir-containing regimen achieved SVR.”
Safety results indicated no serious adverse events or events leading to treatment discontinuation. Headache, fatigue, nausea and insomnia were the most common mild or moderate events reported, but none of these had a rate higher than 36% in any arm, and all were in the group that received ribavirin. The majority of the events (83%) were mild in severity.
The only laboratory abnormalities reported were three instances of grade 2 total bilirubin in the high-dose plus ribavirin group. “No grade 4 abnormalities were observed,” Poordad said.
“In summary, baseline NS3 and/or baseline NS5A RAVs did not appear to impact SVR,” he concluded. “Ribavirin did not appear to increase SVR in this particular study.”
Poordad F, et al. Abstract GS11. Presented at: International Liver Congress; April 13-17, 2016; Barcelona.
Disclosures: Poordad reports financial relationships with AbbVie, Achillion Pharmaceuticals, Anadys Pharmaceuticals, Biolex Therapeutics, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech, Gilead Sciences, GlaxoSmithKline, GlobeImmune, Idenix Pharmaceuticals, Idera Pharmaceuticals, Intercept Pharmaceuticals, Janssen, Kadmon, Medarex, Medtronic, Merck, Novartis, Onyx/Bayer, Santaris Pharmaceuticals, Salix, Scynexis Pharmaceuticals, Tibotec/Janssen, Vertex Pharmaceuticals and ZymoGenetics.