HCV Combo Impresses, but Use Unlikely

By Michael Smith, North American Correspondent, MedPage Today

Published: April 30, 2013

Reviewed by F. Perry Wilson, MD, MSCE; Instructor of Medicine, Perelman School of Medicine at the University of Pennsylvania

Action Points

• Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
• This phase II trial demonstrated a nearly 100% sustained virologic response rate with the use of daclatasvir and sofosbuvir in patients with hepatitis C virus infection refractory to standard therapy.
• Unfortunately, the two drugs are made by different companies and will not be marketed together, making phase III trials difficult.

AMSTERDAM -- Researchers and clinicians got another look here at a combination of investigational oral hepatitis C virus (HCV) drugs that delivered impressive results but will likely never be marketed together.

In a small phase II cohort of very difficult-to-treat patients, the combination of sofosbuvir and daclatasvir led to viral cures in 40 of 41 patients 12 weeks after the end of therapy, according to Mark Sulkowski, MD, of Johns Hopkins University.

The 41st patient did not appear to be tested at week 12 and so was counted as a treatment failure, but was tested 24 weeks after the end of therapy and found to have unquantifiable levels of HCV RNA, Sulkowski reported at the meeting of the European Association for the Study of the Liver.

He added that of the 21 patients who have completed 24 weeks of follow-up after treatment, all have undetectable virus – the so-called 24-week sustained virologic response (SVR₂₄).

In addition, the combination was well-tolerated with few adverse events, and no patient has yet relapsed, he said.

In other words, the all-oral, once-daily combination "looks exceedingly useful," commented Geoffrey Dusheiko, MD, of Royal Free Hospital in London, who was not involved with the study but who moderated the session at which it was presented.

But the combination is running afoul of diverging corporate interests, he noted. Daclatasvir, an NS5A replication complex inhibitor, is owned by Bristol-Myers Squibb, while sofosbuvir, a nucleotide analogue NS5B polymerase inhibitor, is being developed by Gilead Sciences.

The companies have stopped collaborating on the drugs, with each firm preferring to develop its own version of the other's medication.

The result, Dusheiko said, is that "we don't have a large body of phase III data and that may restrict physicians from prescribing this particular combination."

"Unless there's a change in the thinking," he said, it's unlikely the companies will get back together, adding that for clinicians, "It's a conundrum."

Sulkowski reported on 41 patients with the hard-to-treat genotype 1 of the virus who had failed treatment with the current standard of care: a protease inhibitor -- either telaprevir (Incivek) or boceprevir (Victrelis) -- combined with pegylated interferon and ribavirin.

Such patients have no treatment options, Sulkowski said. He and colleagues randomly assigned the 41 volunteers to take sofosbuvir and daclatasvir alone or with ribavirin for 24 weeks. The primary endpoint of the analysis was unquantifiable HCV RNA 12 weeks after the end of therapy – the so-called SVR₁₂.

All patients but one had unfavorable variants of the IL28B gene, which predicts response to interferon treatment, and 33 of 41 had HCV genotype 1a, which is regarded as more difficult to treat than 1b.

Nevertheless, Sulkowski reported, high response rates were seen early in treatment and by the end of therapy all 41 patients had unquantifiable virus, a state that persisted (with the one technical exception) through 12 weeks post-treatment.

There were no serious adverse events in patients taking the combination alone, no discontinuations owing to adverse events, and no grade 3 or 4 adverse events.

In the other arm, the combination plus ribavirin was nearly as well-tolerated with one serious adverse event – a single patient with hypokalemia.

Adverse events reported by at least 10% of patients included fatigue, headache, hair loss, muscle aches, constipation, and diarrhea, Sulkowski said, but all were mild or moderate.

The study had support from Gilead and Bristol-Myers Squibb. Sulkowski reported financial links with the company, as well as with Novartis, BMS, Gilead, Janssen, Vertex, BIPI, Abbott, Merck, Roche/Genentech, BIPI, and Pfizer.

Dusheiko reported financial links with Gilead, GSK, BMS, and Boehringer Ingelheim.

Primary source: European Association for the Study of the Liver
Source reference:
Sulkowski MS, et al "Sustained virologic response with daclatasvir plus sofosbuvir ± ribavirin (RBV) in chronic HCV genotype (GT) 1-infected patients who previously failed telaprevir (TVR) or boceprevir (BOC)" EASL 2013; Abstract 1417.

Source

Also See:

1. Shunned Gilead/Bristol-Myers hep C combo may be too good for docs to ignore (April 28, 2013)
2. Gilead-Bristol Hepatitis C Drug Combo Cures All in Study (April 28, 2013)
3. Gilead-Bristol Hepatitis C Combo Cures 100% of Patients in Study (April 27, 2013)