New hepatitis C drug may halve the length of treatment, but ribavirin still needed

The new hepatitis C protease inhibitor drug telaprevir, when added to the standard treatment of pegylated interferon and ribavirin (IFN/RBV), achieved superior results to standard treatment, according to studies published recently in the New England Medical Journal. Furthermore it did so in 24 weeks, half the time needed for the standard regimen.

The drug, used against the hard-to-treat genotype 1 of hepatitis C, produced a sustained viral response (SVR) – equivalent to a cure – in roughly two-thirds of patients compared with less than a half taking the standard regimen.

However hopes that it might render ribavirin unnecessary were dashed when a regimen using telaprevir and pegylated interferon alone achieved poorer results than the standard regimen containing ribavirin.

Questions also remain about how to develop the new hepatitis C drugs in a co-ordinated manner. Combination drug therapy and trials of drug combinations will be even more necessary in hepatitis C than HIV because it so quickly becomes drug resistant. Thirty-two out of the 34 patients who experienced a rebound of their hepatitis C while still on telaprevir developed drug resistance.

New hepatitis C drugs

Telaprevir, made by Vertex Pharmaceuticals, was formerly known as VX-950 – see this report. It is one of numerous experimental hepatitis C antiviral drugs of a number of different classes currently in trials; the two furthest along in clinical development are telaprevir and Schering-Plough’s boceprevir, formerly SCH 503034 (see this report).

Boceprevir achieved the highest rates of Sustained Viral Response (SVR) yet seen in the treatment of hepatitis C genotype 1 earlier this year when, in the SPRINT trial, it was added to a standard IFN/RBV regimen after a lead-in period of four weeks. The SVR rate after 28 weeks of therapy was 56% and after 48 weeks 75% - twice that of the control group.

However both ribavirin and boceprevir cause anaemia, and 50% of subjects on IFN/RBV and boceprevir developed the condition.

Drug resistance will be an even greater problem in hepatitis C drug development than it was in HIV, as the hepatitis C virus replicates 100 times faster than HIV, with correspondingly higher viral loads. Interferon and ribavirin do not act directly on the viral proteins but the new drugs do, and resistance to single agents happens within days.

In the SPRINT trial the purpose of the four-week IFN/RBV lead-in was to drive the viral replication rate down sufficiently so that by the time boceprevir was introduced, there would be less chance of patients developing resistance to it if they failed to respond to interferon.

In the two telaprevir trials, PROVE 1 and 2, the opposite strategy was used of bringing viral replication down as fast as possible initially, stopping telaprevir after twelve weeks and then in some trial arms continuing with more IFN/RBV.

Trial design

The two PROVE trials had different designs. In both trials there were three different arms using telaprevir and pegylated interferon and one control arm using standard IFN/RBV therapy and a telaprevir placebo.

In the American PROVE 1 trial (McHutchison) the four trial arms consisted of:

• Twelve weeks of telaprevir plus IFN/RBV therapy (the 12/12 arm)
• Twelve weeks of telaprevir plus IFN/RBV therapy then twelve more weeks of IFN/RBV therapy (the 12/24 arm)
• Twelve weeks of telaprevir plus IFN/RBV therapy then 36 more weeks of IFN/RBV therapy (the 12/48 arm)
• The control or standard-or-care arm consisted of the same regimen as the 12/48 arm except that the telaprevir was replaced with a placebo.

In the European PROVE 2 trial (Hézode) the four trial arm consisted of:

• A 12/12 arm as in PROVE 1
• A 12/24 arm as in PROVE 1
• An arm consisting of twelve weeks of telaprevir plus pegylated interferon without ribavirin (the 12/12/no RBV arm)
• The same control arm as PROVE 1.

The initial twelve-week phase was double-blinded and placebo-controlled, but after that it became unblinded because of the different regimen lengths.

Trial populations

The two trial populations were quite similar. Trial participants had to be naïve to hepatitis C treatment, not be co-infected with hepatitis B or HIV, and not have liver cirrhosis. Their average age was 45-50 and about 40% were women. Twenty per cent of the PROVE 1 population were non-white, compared with only 5% in PROVE 2, and 20% of the PROVE 1 population had severe fibrosis (grade 3-4) compared with 8% in PROVE 2.

HCV viral loads were similar with an average of 3.65 million in PROVE 1 and 2.51 million in PROVE 2. Although all patients had genotype 1 of HCV, the proportions with the subtypes 1a and 1b differed: in PROVE 1 64% had genotype 1a, in PROVE 2 44%.

There were 250 patients in PROVE 1 split evenly between the 12/24, 12/48 and control arms, but only 17 patients in the 12/12 arm as this was not authorised as standard protocol initially. PROVE 2 had 323 patients split evenly between the four arms.

Results

The SVR results were as follows:

PROVE 1

• 12/12 arm: 35%
• 12/24 arm: 61%
• 12/48 arm: 67%
• Control arm: 41%

PROVE 2

• 12/12 arm: 60%
• 12/24 arm: 69%
• 12/12/no RBV arm: 36%
• Control arm: 48%

The early viral response rates at week 4 and week 12 were extremely high, with up to 80% undetectable in the telaprevir/IFN/RBV arms and about 70% at the end of therapy. This compared with about 50% undetectable at the end of therapy in the control arms and 60% in the no-ribavirin arm in PROVE 2.

However the relapse rates, where relapse was defined as viral reappearance after the end of therapy, were higher in the control arms (about 22%) and the 12/12 arms (about 30%) than in the longer arms (2-6% in the 12/24 and 12/48 arms in PROVE 1 and 14% in the 12/24 arm in PROVE 2, though only 7% in patients who had been undetectable by week 4.) There was a particularly high relapse rate of 48% in patients in PROVE 2 who did not take ribavirin.

Virologic failure, resistance and side effects

In PROVE 1 twelve patients on telaprevir (6.8% of those taking the drug) had ‘viral breakthrough’ or a rise in viral load while still on the drug; in PROVE 2 six patients on telaprevir in the ribavirin-containing regimens had viral breakthrough (3.7%) but 19 in the no-ribavirin group (24%).

All but two people who had a viral rebound while still on telaprevir developed one or two resistance mutations to it. In PROVE 2, among the 42 patients who had 'viral relapse', or a post-treatment reappearance of hepatitis C, seven patients developed high-level resistance to telaprevir, 33 low-level resistance and only two no resistance.

Rather more people taking telaprevir discontinued therapy than those in the control arms: 21% versus 11% in prove 1 and 12% versus 7% in prove 2. The only side-effect that stood out in the telaprevir patients was itching and rash. This was classed as ‘severe’ in 7% of telaprevir patients in Prove 1 and 15% in PROVE 2 compared with 1% and zero patients respectively in the control groups.

PROVE 3

Despite problems with side effects and resistance, it can be seen that in the PROVE 1 and 2 studies telaprevir enabled at least 30% more patients to achieve an SVR rate than would have been possible on standard therapy. Furthermore it did so in only 24 weeks of therapy rather than 48, as is standard for hepatitis C genotype 1.

Perhaps more remarkable is PROVE 3, a trial whose results are yet to be published. PROVE 3 is a trial of telaprevir plus standard therapy in patients who have failed hepatitis C therapy before. ts design is the same as PROVE 1 except that the 12/12 arm is omitted.

In late-breaker results presented at the European Association for the Study of the Liver (EASL) conference in April, PROVE 3 principal investigator Michael Manns announced that 51-52% of patients in the 12/24 and 12/48 arms had achieved an SVR compared with 14% in the control group. This immediately increases the number of people who might be able to achieve an SVR and be cured of their hepatitis C.

Vertex are planning several phase III studies including one with lead-in dosing like the boceprevir trial. However many dilemmas still remain in hepatitis C treatment such as how to combine investigative drugs, how to get around the sequential-monotherapy and resistance problem, and how to start trials in HIV/hepatitis C co-infected people.