SAPPHIRE II trial results show sustained virologic response in 96% of treatment-experienced patients with genotype 1 hepatitis C who were treated with interferon-free, triple-drug regimen.
Approximately 160 million people suffer with chronic hepatitis C (HCV) globally. The majority of patients have the genotype 1 (GT1) strain of the hepatitis C virus (HCV). Current interferon-based treatment for the disease is associated with substantial treatment toxicity. Furthermore, many patients with the disease are not able to tolerate treatment with interferon due to co-existing medical conditions.
On Thursday at the 2014 European Association for the Study of the Liver (EASL) International Liver Congress in London, Professor Stefan Zeuzem, MD, Professor of Medicine (JW Goethe University, Frankfurt, Germany) presented promising results from the SAPPHIRE II trial, the first global, multicenter, phase 3, randomised, placebo-controlled trial of an all-oral three direct-acting-antiviral (3D), multi-target antiviral, interferon-free regimen for treatment-experienced patients with G1 HCV.
The 12-week 3D regimen used in the trial combines ritonavir boosted ABT-450 with ritonavir booster (ABT-450/r), dasabuvir (formerly ABT-333) and ombitasvir (formerly ABT-267) for the treatment of chronic hepatitis C.
ABT-450 is a potent NS3/4A protease inhibitor identified by AbbVie and Enanta; ritonavir is a potent inhibitor of cytochrome P450 3A4 (CYP3A4) and CYP2D6 that boosts the serum levels of other protease inhibitors (PIs). Ombitasvir is a potent NSSA inhibitor and dasabuvir is a non-nucleoside NSSB polymerase inhibitor. Combining ABT-450 with ritonavir (ABT-450/r) produces a drug that can be taken once per day with increased the exposure of NS3/4A to patients. The combination of three different mechanisms of action of this 3D combination interrupts the HCV replication process and optimizes a sustained virologic response during the 12-week regimen (SVR12) in HCV patients.
Zeuzem addressed a packed auditorium at the first general session of the 2014 EASL International Liver Congress, highlighted by the session co-chairman Markus Perk, as the largest congress on the liver in the organisation’s history, with over 10,000 registered participants from all over the world. Zeuzem said “this multi-target 3D treatment approach has been used in more than 2,700 patients worldwide and a number of studies have convincingly shown that the regimen is well-tolerated and potent.”
In SAPPHIRE-II, 394 treatment experienced adult patients with GT1a or GT1b HCV and no cirrhosis who had either failed treatment, or were partially or non-responsive to partially responsive pegylated interferon and ribavirin were randomised either to placebo or to the 3D treatment arm consisting of co-formulated ABT-450/r/ombitasvir, 150mg/100 mg/25 mg OD; dasabuvir 250mg BID for a period of 12-weeks. Patients initially in the placebo group then received the 12-week 3D treatment regimen. The primary analysis of the SVR rates for both study groups was at week 24 of the study; all patients received a follow-up assessment at week 48.
SVR12 rates for patients with GT1-HCV subgenotype showed that 96.3 % of patients achieved a sustained biological response; SVR12 rates were 96.7% of patients with GT1-HCV. Zeuzmen said, “These results clearly show the 3D treatment as surpassing the superiority threshold as well as the non-inferiority threshold”. Zeuzmen said “another important result was the comparison between 3D regimens in these patients as compared to these patients’ prior response to pegylated interferon and ribavirin treatment before the SAPPHIRE trial”. Ninety-five percent, 100%, and 95.2% of pegylated interferon and ribavirin-relapsed, partial responders, and null responders, respectively, achieved a sustained response with 3D (SVR12).
Zeuzman said, “Not a single patient showed a virologic breakthrough during the 12 weeks of therapy.” Overall there were only 7 relapses and only 4 patients discontinued treatment during the trial. The 3D treatment is highly tolerable; 92% of patients in the placebo group reported adverse events whereas only 91% of patients in the treatment group reported adverse events. The number of adverse events was low and consisted mainly of fatigue, headache, nausea, and puritis (which was mild and disappeared after therapy). Only 3 patients were forced to discontinue the trial due to adverse events; serious adverse events were observed in 6 patients; no pattern was noticed. There were no cases of drug toxicity during the trial.
In response to a question about dealing with problem of drug-drug interactions which is often a feature of real-world situations in the clinic, Zeuzman noted that “experienced physicians have really learned to manage these challenges in clinical situations and I would not think that the proportion of patients not eligible for trial of a 12-week treatment regimen would be in a substantial number… in the low single digit percentage rates.”
The SVR12 intend to treat rate in this trial of treatment experienced patients with HCV was 96.3%, SVR rates were high regardless of HCV genotypes: 96.3% (GT1-HCV) and 96.7% GT2-HCV (and the SVR rates were high across all pegylated interferon and ribavirin response groups).
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