Miriam E. Tucker

April 13, 2014

LONDON — A single daily pill could be a cure for nearly all patients infected with hepatitis C genotype 1 in as little as 8 weeks, according to dramatically positive results from 3 large phase 3 clinical trials of Gilead's fixed-dose combination of the direct-acting antiviral drugs sofosbuvir and ledipasvir.

"The good thing is that we're really advancing toward a cure. Actually, when you look at the data, we're almost there for most of our patients," said Markus Peck-Radosavlevic, MD, secretary-general of the European Association for the Study of the Liver, who was not involved in the trials.

The results of the 3 ION trials were presented here at the European Association for the Study of the Liver (EASL) International Liver Congress 2014 and simultaneously published in the New England Journal of Medicine.

"With cure rates well in excess of 90% with as little as 8 weeks of treatment for some patients, these data represent a significant advance in the race to develop a new, all-oral treatment for hepatitis," Dr. Peck-Radosavlevic said during a press briefing.

ION-3: 8 vs 12 Weeks

Results from the ION-3 study were presented by Kris Kowdley, MD, from the Digestive Disease Institute at the Virginia Mason Medical Center in Seattle, and were published online April 11.

The open-label study investigated a fixed-dose combination of the nucleotide analogue polymerase inhibitor sofosbuvir and the NS5A inhibitor ledipasvir in 647 previously untreated patients without cirrhosis.

Patients were randomly assigned to receive the ledipasvir and sofosbuvir combination for 8 weeks, with or without ribavirin, or the combination alone for 12 weeks. The primary end point, sustained viral response at 12 weeks (SVR12), was achieved in 94% of those who received 8 weeks of the combination alone, 93% of those who received 8 weeks of ledipasvir and sofosbuvir plus ribavirin, and 95% of those who continued ledipasvir and sofosbuvir up to 12 weeks.

There were no virologic failures during treatment, and just 3 patients discontinued treatment because of adverse events. Serious adverse events occurred in 10 patients, but none of these events were related to the treatment, Dr. Kowdley said.

About half of the 5% to 7% of patients who did not achieve SVR12 were actually lost to follow-up and were not necessarily treatment failures, suggesting that "8 weeks of treatment seem to be enough, even without ribavirin," said Dr. Peck-Radosavlevic. "For genotype 1, I think it's safe to say you don't need ribavirin."

ION-2: Treatment-Experienced Patients

Results from ION-2 were presented by Nezam Afdhal, MD, from the Beth Israel Deaconess Medical Center in Boston, and were published online April 12.

The ION-2 study, which was also open label, looked at 440 treatment-experienced patients. Twenty percent of the patients had compensated cirrhosis, and 79% had hepatitis C genotype 1a infection. All patients had failed to achieve an SVR12 after treatment with peginterferon and ribavirin, with or without a protease inhibitor. They were randomly assigned to receive ledipasvir and sofosbuvir with or without ribavirin for 12 or 24 weeks.

After 12 weeks, SVR12 was 94% for those who received 12 weeks of the ledipasvir and sofosbuvir combination, 96% for those who received the ledipasvir and sofosbuvir combination with ribavirin, and 99% for those who received 24 weeks of treatment, both with and without ribavirin.

Results were similar for patients with hepatitis C genotypes 1a and 1b. Those with cirrhosis did slightly worse, with SVR12 rates of 86% with ledipasvir and sofosbuvir and 82% for ledipasvir and sofosbuvir with ribavirin. However, SVR12 rates were 100% in both treatment groups with cirrhosis at 24 weeks, Dr. Afdhal reported.

A total of 11 patients relapsed after treatment. All were in the 12-week treatment group, and 7 had cirrhosis, he said.

Virologic failure occurred in 1 patient. Treatment-emergent adverse events occurred in 9 patients (2%), but none discontinued treatment. Hemoglobin levels of less than 10 g/dL occurred in 5% of the patients who received ledipasvir and sofosbuvir with ribavirin but in 0% of those who received ledipasvir and sofosbuvir alone.

ION-1: Treatment-Naive Patients

In a late-breaking presentation, Alessandra Mangia, MD, from the liver unit at the Casa Sollievo della Sofferenza Hospital, in San Giovanni Rotondo, Italy, reported the results of ION-1, an open-label trial of 865 previously untreated patients with hepatitis C genotype 1, including 16% with cirrhosis.

The results were published online April 12.

In the trial, patients received ledipasvir and sofosbuvir with or without ribavirin for 12 or 24 weeks.

Rates of SVR12 were 99% in the group that received 12 weeks of ledipasvir and sofosbuvir, 97% in the group that received 12 weeks of the combination plus ribavirin, 98% in the group that received 24 weeks of ledipasvir and sofosbuvir, and 99% in the group that received 24 weeks of ledipasvir and sofosbuvir plus ribavirin.

The most frequent adverse events reported were headache (25%), fatigue (23%), and nausea (12%). Treatment-emergent adverse events occurred in 4% of patients. No patient receiving 12 weeks of treatment and 10 patients receiving 24 weeks of treatment discontinued therapy because of an adverse event.

Hemoglobin levels of less than 10 g/dL occurred in 8% of patients taking ledipasvir and sofosbuvir with ribavirin, and in 0% of those taking the combination without ribavirin.

The ION-1 data "are very, very convincing and almost unbelievable," said Dr. Peck-Radosavlevic.

The Real World

During the press briefing, a reporter asked whether these overwhelmingly positive results would hold true in the real world, considering that price constraints will likely mean that ledipasvir plus sofosbuvir and other combinations will be reserved for patients with the most advanced liver damage.

The ION data suggest that for compensated cirrhotic patients, "there's no reason to believe that [the results] in the real world will be any different from what you see in the phase 3 trials," Dr. Dr. Peck-Radosavlevic responded.

Studies are ongoing for decompensated patients, who are "probably the most difficult to treat and arguably at highest need of treatment," he said.

"We will see next year. Maybe the cure rates will be similar, maybe they will be slightly lower, but I think by and large you will have very few treatment failures in real life. Also, the drugs have very few side effects, and people will not be reluctant to take them, especially if you only have to take them for 8 weeks," said Dr. Peck. "These are just fantastic results."

Dr. Peck-Radosavljevic reports consulting for or receiving speaker honoraria from BMS, AbbVie, Gilead, Merck, Roche, Lilly, Bayer, Boehringer, and GlaxoSmithKline. Dr. Kowdley reports receiving fees for serving on advisory boards through his institution from Boehringer Ingelheim, Gilead Sciences, Ikaria Pharmaceuticals, Janssen, Merck, Vertex Pharmaceuticals, Trio Health, Pharmasset, and Tekmira Pharmaceuticals; consulting fees through his institution from Novartis; and grant support through his institution from Beckman Coulter, Bristol-Myers Squibb, Boehringer Ingelheim, Gilead Sciences, Ikaria Pharmaceuticals, Intercept Pharmaceuticals, Janssen, Merck, Mochida, Vertex Pharmaceuticals, Pharmasset, Conatus Pharmaceuticals, Genentech, and GlaxoSmithKline. Dr. Afdhal reports grant support from Gilead during the conduct of the study; grant support from Abbott; grant support and personal fees from Gilead, Merck, Vertex, and Bristol-Myers Squibb; personal fees from Janssen, Novartis, Boehringer Ingelheim, and Idenix; and personal fees and other support from Springbank and Medgenics outside the submitted work. Dr. Mangia reports grant support from Roche and personal fees from Gilead, Merck Sharp & Dohme, and Janssen outside the submitted work.

European Association for the Study of the Liver (EASL) International Liver Congress 2014: Abstracts 56 and 109. April 11 and April 12, 2014.

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