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.

Do you want to learn more about telaprevir? Click here.

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Stakeholder Insight: Hepatitis B & C in Asia - China, South Korea, Taiwan and Turkey

Dendreon: landmark cancer vaccine approval but high costs may hinder uptake

Having been approved by the FDA in castration-resistant prostate cancer (press release), Dendreon's Provenge represents the first therapeutic cancer vaccine to reach the market (click here for related reports). This is a significant step forward: the current standard of care is Taxotere-based chemotherapy, which is associated with significant toxicity. However, it remains to be seen how frequently Provenge is used.

Provenge (sipuleucel-T; Dendreon) is composed of autologous peripheral blood mononuclear cells, including antigen-presenting cells that have been activated during culture with a recombinant human protein, PAP-GM-CSF. PAP-GM-CSF consists of prostatic acid phosphatase (PAP), an antigen expressed on approximately 95% of prostate tumor cells, linked to granulocyte-macrophage colony-stimulating factor (GM-CSF), an immune cell activator. Upon administration, the PAP-activated cells cause activation of T-cells and other immune system components to recognize the target antigen and destroy prostate tumor cells.

Manufacture of Provenge requires collection of antigen-presenting cells from individual patients, via leukapheresis, a blood collection process used to isolate white blood cells. The cells are then transported to the Dendreon manufacturing facility, presumably in cold storage, where co-culture with a PAP-containing recombinant fusion protein occurs. Manufacture of Provenge takes approximately two days, after which the vaccine is delivered to the physician's office for infusion into the patient. This entire process is carried out three times over the course of a four-week period, in order to provide three vaccinations to each patient.

Provenge has had a troubled development history to date. Dendreon initially filed a Biologics License Application (BLA) in January 2007 on the basis of Phase III D9901 study results, which showed an improvement in overall survival but failed to meet its primary endpoint of time to progression. The FDA issued an approvable letter in May 2007, requesting additional clinical data. This was met with controversy from the public; indeed, prostate cancer patient group Care to Live filed a lawsuit against the FDA, demanding that Provenge be approved.

Following this, the FDA stated that it would accept interim or final data from the ongoing Phase III IMPACT study to amend Provenge's BLA. Positive results were announced in April 2009, showing that Provenge conferred a 4.1 month survival benefit over placebo in asymptomatic or minimally symptomatic metastatic CRPC, thus meeting the study's primary endpoint. This made Provenge the first therapeutic cancer vaccine to demonstrate an improvement in overall survival for metastatic CRPC.xx Despite now having received FDA approval in asymptomatic or minimally symptomatic metastatic, castration-resistant prostate cancer (CRPC), it remains to be seen how frequently Provenge will be used in the treatment of this disease. At present, patients are typically treated with standard Taxotere (docetaxel; Sanofi-Aventis)-based chemotherapy. Taxotere is relatively simple in terms of manufacture and use, capable of immediate, 'off the shelf' administration. In comparison, an autologous vaccine like Provenge requires a costly and labor-intensive manufacturing process.

Dendreon has indicated that Provenge will be priced at $31,000 per dose, equating to $93,000 per complete course of treatment. In comparison, Taxotere costs under $3,000 per cycle of therapy, with an average of six cycles of treatment therefore costing around $18,000. Dendreon has stated that Provenge is more cost effective due to the lack of required premedication and supportive care costs compared to Taxotere.

Furthermore, Provenge's favorable toxicity profile may influence physician preference in comparison to Taxotere's adverse side effects, particularly in patients who are asymptomatic. Taxotere is associated with significant toxicity, while Provenge causes only mild grade 1/2 side effects. Provenge is therefore likely to be used in those patients precluded from Taxotere therapy.

Provenge's approval in asymptomatic or minimally asymptomatic patients indicates that the vaccine may be used before Taxotere. Presumably once patients progress and become symptomatic after Provenge, Taxotere will still be required. Given that healthcare systems are becoming increasingly cost-conservative, the high cost of Provenge may hinder its uptake in some patient groups, particularly those that do not qualify for the patient access plan that Dendreon has set up in light of the approval.

See also our editorial: Advaxis lights up the future for cervical cancer and maybe some head and neck cancers

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