Impressive SVR12 data for once-daily combination to treat HCV genotype 1 patients

London, UK, Saturday 12 April 2014: Results from three Phase III clinical trials (ION-1, ION-2 and ION-3) evaluating the investigational once-daily fixed-dose combination of the nucleotide analogue polymerase inhibitor sofosbuvir (SOF) 400mg and the NS5A inhibitor ledipasvir (LDV) 90mg, with and without ribavirin (RBV), for the treatment of genotype 1 chronic hepatitis C virus (HCV) infection have been presented at the International Liver CongressTM 2014.

"With cure rates well in excess of 90% with as little as eight weeks of treatment for some patients, these data represent a significant advance in the race to develop a new, all-oral treatment for Hepatitis C," said Professor Markus Peck-Radosavljevic, Secretary-General of the European Association for the Study of the Liver and Associate Professor of Medicine, University of Vienna, Austria.

"The results of the ION studies demonstrated highly satisfactory cure rates with a fixed dose combination of sofosbuvir/ledipasvir among patients with genotype 1 HCV infection without the use of either injectable interferon, which causes miserable flu-like symptoms, or ribavirin, an antiviral pill associated with a variety of troublesome side effects, including anaemia and rash," Professor Peck-Radosavljevic continued. "As a result of this marked improvement in tolerability, many more people are likely to seek treatment with this ribavirin-free regimen, which involves just one pill once a day."

Across the three ION studies, 1,952 patients with genotype 1 HCV infection were randomised to receive LDV/SOF with or without RBV for eight, 12 or 24 weeks of therapy. Of these, 1,512 patients were treatment-naïve, 440 were treatment experienced and 224 had compensated cirrhosis.

Of the 1,952 patients randomised in ION-1, ION-2 and ION-3, 1,886 patients (96.6%) achieved the primary efficacy endpoint of SVR12. Of the 66 patients (3.4%) who failed to achieve SVR12, 38 patients (1.9%) experienced virological failure: 36 due to relapse and two patients due to on-treatment breakthrough (with documented non-compliance). 28 patients (1.4%) were lost to follow-up.

Fewer adverse events were observed in the RBV-free, fixed-dose combination arms compared to the RBV-containing arms in all the ION studies. Adverse events observed in those taking LDV/SOF were generally mild and included fatigue and headache. In the RBV-containing arms of the ION studies, the most common adverse events were fatigue, headache, nausea and insomnia. Anaemia, which is a common side effect associated with RBV, was reported in 0.5% of patients in the LDV/SOF arms versus 9.2% of patients in the RBV-containing arms. Less than 1% of patients in the studies discontinued treatment due to treatment-emergent adverse events.

Genotype 1 is the most common, but hardest to treat, strain of the hepatitis C virus. Sofosbuvir belongs to a class of directly acting anti-viral (DAA) drugs known as nucleotide analogue polymerase inhibitors, which are designed to block an enzyme the hepatitis C virus needs to copy itself. Ledipasvir belongs to a promising new class of DAA drugs that work by blocking the NS5A protein, which the hepatitis C virus also needs to replicate.

ION-2 STUDY[i]

• The ION-2 study evaluated 440 treatment-experienced genotype 1 HCV patients, including 88 with compensated cirrhosis, who had failed past therapy with regimens containing Peg-IFN (including Peg-IFN plus a protease inhibitor)
• Patients received LDV/SOF with or without RBV for 12 or 24 weeks
• After 12 weeks of therapy, SVR-12 was 96.4% and 93.6% for SOF+LDV+RBV and SOF+LDV
• After 24 weeks of therapy, SVR-12 was 99.1% and 99.1% for SOF+LDV+RBV and SOF+LDV
• One patient experienced on-treatment virological failure
• No patients discontinued treatment due to an adverse event
• Nine patients (2%) had treatment-emergent SAEs
• Haemoglobin <10 g/dL occurred in 5% of patients taking LDV/SOF+RBV, and no patients taking LDV/SOF

ION-1 STUDY[ii]

• The ION-1 study looked at 865 previously untreated patients, including 136 with cirrhosis
• Patients received LDV/SOF with or without RBV for 12 or 24 weeks
• After 12 weeks of therapy, SVR-12 was 97.2% and 98.6% for SOF+LDV+RBV and SOF+LDV
• After 24 weeks of therapy, SVR-12 was 99.1% and 97.7% for SOF+LDV+RBV and SOF+LDV
• The most frequent AEs reported for LDV/SOF were headache (25%), fatigue (23%), and nausea (12%)
• 33 patients (4%) had treatment-emergent SAEs
• No patients receiving 12-Weeks of treatment and 10 patients receiving 24-Weeks of treatment discontinued therapy due to an AE
• Haemoglobin <10 g/dL occurred in 8% of patients taking LDV/SOF+RBV and no patients taking LDV/SOF

ION-1 STUDY - Patient reported outcomes[iii]

• Patient reported outcomes (PRO) were evaluated using: Chronic Liver Disease Questionnaire-HCV (CLDQ-HCV), Short Form-36 (SF-36), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), and Work Productivity and Activity Index: Specific Health Problem (WPAI: SHP)
• Throughout treatment, some of the PRO scores, especially those related to fatigue, activity and work productivity, were superior for RBV-free regimen (by up to 13.1%; p-values ≤0.5 to < 0.0001)
• During treatment with the RBV-containing regimen, significant decrements in PROs were noted from baseline scores (up to -8.1%, p< 0.0001)
• In contrast, most of PROs for the RBV-free regimens improved (up to +6.1%, p< 0.0001). This improvement was noted as early as treatment week 2, and maximised by end of treatment
• Regardless of the regimen, patients who achieved SVR-12 showed significant improvement of PROs (+3.1% to +9.6%, p=0.045 to < 0.001)

ION-3 STUDY[iv]

• In ION-3, 647 previously untreated patients without cirrhosis received LDV/SOF with or without RBV for 8 weeks or without RBV for 12 weeks
• 94% achieved SVR-12 after just eight weeks of treatment with LDV/SOF, rising to 95.4% with a 12-week regimen of LDV SOF.
• There were no virological failures during treatment
• Treatment was well tolerated: three patients discontinued due to adverse events
• 10 patients had SAEs: none were related to treatment
• Haemoglobin <10 g/dL occurred in 5% of patients receiving LDV/SOF+RBV and in a single patient who received LDV/SOF

Disclaimer: the data referenced in this release is based on the submitted abstract. More recent data may be presented at the International Liver Congress™ 2014.

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[i] N.Afdhal et al. ALL ORAL FIXED-DOSE COMBINATION SOFOSBUVIR/LEDIPASVIR WITH OR WITHOUT RIBAVIRIN FOR 12 OR 24 WEEKS IN TREATMENT-EXPERIENCED GENOTYPE 1 HCV-INFECTED PATIENTS: THE PHASE 3 ION-2 STUDY. Abstract presented at the International Liver CongressTM 2014

[ii] A.Mangia et al. ALL ORAL FIXED-DOSE COMBINATION SOFOSBUVIR/LEDIPASVIR WITH OR WITHOUT RIBAVIRIN FOR 12 OR 24 WEEKS IN TREATMENT-NAIVE GENOTYPE 1 HCV-INFECTED PATIENTS: THE PHASE 3 ION-1 STUDY. Abstract presented at the International Liver CongressTM 2014

[iii] Z.Younossi et al. LEDIPASVIR (LDV) AND SOFOSBUVIR (SOF) COMBINATION IMPROVES PATIENT-REPORTED OUTCOMES (PRO) DURING TREATMENT OF CHRONIC HEPATITIS C (CH-C) PATIENTS: RESULTS FROM THE ION-1 CLINICAL TRIAL. Abstract presented at the International Liver CongressTM 2014

[iv] K.Kowdley et al. LEDIPASVIR (LDV) AND SOFOSBUVIR (SOF) COMBINATION IMPROVES PATIENT-REPORTED OUTCOMES (PRO) DURING TREATMENT OF CHRONIC HEPATITIS C (CH-C) PATIENTS: RESULTS FROM THE ION-3 CLINICAL TRIAL. Abstract presented at the International Liver CongressTM 2014