Promising data reads out from ADVANCE as first generation oral HCV therapies march on

Hepatitis C (HCV) represents a major global problem infecting approximately 180 million people around the world. The United States accounts for approximately 3.9 million people with chronic infection. Remarkably 75% of these patients do not even know it. The incidence of infection has now stabilized in the developed world with the exception of certain sub-groups such as intravenous drug users. Consequently those patients who are infected have increasingly chronic disease and this carries significant risks such as increased fibrosis and hepatocellular cancer.

Treatment options for HCV are currently limited to one of two pegylated interferons (Pegasys and PEG-INTRON) and in some geographies, non-pegylated interferon. Standard of care dictates that the interferon of choice should be taken alongside ribavirin for 24 to 48 weeks depending on the HCV genotype. Treatment is arduous, carrying multiple adverse events over an extended period of time; moreover treatment is more often than not unsuccessful and underused. In the US cure rates are approximately 40-45% in genotype 1 patients, falling drastically in patients who have already failed once course of treatment. Genotype 2 and 3 patients fare considerably better however these patients are in the minority, at least in the US and Europe. As if the cure rates in genotype 1 patients was not bad enough, success becomes increasingly common as the disease becomes more chronic.

Against the backdrop of poor response and difficult treatment it is hardly surprising that less than 10% of diagnosed patients are treated. This explains the intense excitement around the new wave of oral antiviral approaching the market. The two main classes of therapeutic agents are the HCV protease inhibitors and polymerase inhibitors. The proteases lead the way by a couple of years and this class is in turn lead by telaprevir (Vertex/Tibotec/Mitsubishi Tanabe) and boceprevir (Merck) which are running neck and neck to reach the market first.

Having passed through its Phase 2 study program, PROVE, Vertex submitted the Phase 3 telaprevir protocol to the FDA in Jan 2008. The program comprises 3 studies: ADVANCE and ILLUMINATE (treatment naïve) and REALIZE (treatment experienced). The aim of the treatment naive studies was to increase cure rate while at the same time reducing the duration of treatment. Consequently, ADVANCE compared 48 weeks standard of care versus two telaprevir based treatment arms. One arm treated patients for 8 weeks with triple therapy prior to stopping telaprevir; the second arm continued triple therapy for 12 weeks. In both cases the intention was to stop all treatment at week 24 although ADVANCE included a novel protocol where treatment duration was personalized. Those patients not clearing virus by week 4 and remaining virus negative until at least week 12 (ie eRVR) received standard of care for 48 weeks.

ADVANCE opened March 13th, completed enrolment in Oct 2008 and a few days ago, Vertex announced top line data. SVR rates (ie undetectable virus for at least 24 weeks after end of treatment) were an impressive 69-75% (depending on how long telaprevir was on board) compared to the usual depressing 44% with standard of care.

Vertex and most analysts are excited. The SVR rates in ADVANCE are slightly greater than the 67-68% reported from PROVE 1 and 2. This has been suggested to reflect improved management of adverse events, notably rash, and reduced drop outs (which were counted as treatment failures). Perhaps a little disappointing, SVR rates were lower than the 81-85% reported in another Phase 2 study, C208, which like ADVANCE incorporated an individualized treatment protocol. This difference has been put down to the relatively large numbers of difficult to treat patients in ADVANCE (eg African Americans; patients with fibrosis etc).

During conference calls around the ADVANCE data release it was commented that 70% of patients achieving SVR were treated for 24 weeks. On the surface this sounds impressive however bearing in mind that patients in the standard of care arm received 48 weeks of treatment by definition, we calculate that ≈50% of telaprevir treated patients were on treatment for 48 weeks. This will be viewed with interest by those at Merck considering that Vertex has consistently messaged that one advantage of telaprevir is its ability to offer high cure rates with short treatment duration.

One particularly remarkable aspect of ADVANCE is that treatment discontinuation rates due to adverse events were just 7% and 8% in the 12 and 8 week telaprevir arms vs 4% in controls. On the surface this is considerably reduced compared to PROVE 1 and 2 rates of 12-21%. Of particular note, rash related discontinuation was reduced from 7% to 1.4% reflecting successful us of the rash management protocols developed for the Phase 3 program.

However, LeadDiscovery urges caution in interpreting the discontinuation rates as figures reflect stopping all treatment. Comments were made during the Vertex calls that discontinuation rates were approximately doubled if patients discontinuing just telaprevir were included. Even against this backdrop of potentially high telaprevir discontinuation rates, SVR rates do not appear to particularly suffer. It remains to be seen however what effect discontinuing just telaprevir has on both SVR rates and also the duration of treatment.

An editorial on HCV would not be complete without mentioning IL28B.

Last year data were published showing that the 30% of patients carrying a particular allele of this gene stood a very good chance of being cured with standard of care. This could be a threat to telaprevir. Would payors allow telaprevir use in patients with this allele? Moreover this story plays right into the arms of Merck and boceprevir, Vertex's chief rival

Firstly Merck claims to have the intellectual rights to IL28B testing; secondly boceprevir studies incorporate a 4 week lead in phase during which patients receive just standard of care. Conceivably, a paradigm could emerge through which patients are tested for IL28B prior to treatment and if they achieve an early antiviral response at 4 weeks (RVR) there is a very good chance that the patients will not require a protease inhibitor. This offers the clinician greater flexibility in treating patients and payors an opportunity to cut costs.

So how is Vertex responding to this? Well, based on comments made it appears that the company will be retrospectively genotyping patients from ADVANCE in order to determine whether patients carrying the good IL28B may achieve cure more rapidly. This is turn opens up the path towards dropping treatment duration below even the 2 weeks evaluated in ADVANCE. The FDA is apparently working with Vertex in order to understand the impact of IL28B genotype on anti-viral activity in STATC regimens. It is unlikely that data will be available for AASLD 2010. This particularly story is sure to run however.

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