EASL 2015: Pre-Conference Highlights for the 2015 International Liver Congress.
By Michael Haydock, Lead Analyst
20 April 2015
I am the Lead Analyst of the immunology and inflammation and infectious diseases and vaccines teams at Datamonitor Healt...
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The recent US and EU approvals of Harvoni (sofosbuvir/ledipasvir; Gilead) and Viekira Pak (paritaprevir/ritonavir/ombitasvir + dasabuvir; AbbVie) have been watershed moments for the treatment of hepatitis C, ushering in a new era of highly effective and tolerable interferon-free regimens. With the safety and efficacy of Gilead’s and AbbVie’s regimens now widely established, Merck & Co’s grazoprevir/elbasvir will take center stage at the 2015 International Liver Congress, as investors and physicians alike scrutinize a plethora of Phase II and Phase III data. Datamonitor Healthcare expects that Phase III C-EDGE data will position grazoprevir/elbasvir as the main rival to Harvoni for the treatment of genotype 1 (GT-1) patients, but Merck & Co must be willing to offer substantial discounts to gain reimbursement from cost-conscious payers.
Other key hepatitis C presentations will include data from studies of Gilead’s and Achillion’s early-phase pan-genotypic regimens, which are pushing the boundaries of shortened treatment durations in a bid to show differentiation from competitors. Gilead will present late-breaking data from a Phase II study of short treatment durations of sofosbuvir/GS-5816 plus the pan-genotypic protease inhibitor GS-9857, while Achillion will present updated data from the Phase II PROXY study assessing six- or eight-week courses of ACH-3102 plus Sovaldi (sofosbuvir; Gilead) in GT-1 patients. Together with previously released C-SWIFT data, both of these studies will be crucial in informing the minimum acceptable treatment duration for non-cirrhotic and cirrhotic patients. The optimal length of treatment has particularly important implications for payers, as shorter treatment durations would significantly decrease the cost of treatment and allow greater numbers of patients to access care.
Despite competitive efficacy, grazoprevir/elbasvir will be forced to compete on price
Based on the impressive Phase II C-WORTHy data, which showed that 90−97% of GT-1 patients treated with 12 weeks of grazoprevir/elbasvir ± ribavirin achieved viral cure, Datamonitor Healthcare expects that Merck & Co’s combination will show comparable efficacy to Harvoni in the Phase III C-EDGE studies. However, with no improvements in treatment duration or pill burden, Merck & Co will be forced to undercut Gilead in order to penetrate the market. Discounts will be particularly important in the US, where Gilead and AbbVie have negotiated exclusive reimbursement agreements with several major payers in exchange for steep price cuts.
In advance of the meeting, Merck & Co has released partial sustained virologic response (SVR) data from the C-EDGE treatment-experienced study, which show that 95−98% of patients achieved SVR4 after 12 weeks of treatment with grazoprevir/elbasvir ± ribavirin. High cure rates were maintained in cirrhotic patients (92−97%), suggesting that a 12-week treatment duration is sufficient for most patients. These data compare favorably with cure rates observed in Harvoni’s and Viekira Pak’s pivotal Phase III studies, although Datamonitor Healthcare awaits a detailed breakdown of cure rates by GT-1 subtype in cirrhotic patients to assess if a longer 24-week duration would be beneficial for GT-1a patients. Based on the pre-released data, 12 weeks of grazoprevir/elbasvir is highly effective in treatment-experienced GT-1b cirrhotics, but four GT-1a cirrhotic patients underwent relapse post-treatment. These data suggest that Merck & Co could seek a more attractive label than Harvoni, which is currently recommended as a 24-week treatment course in all treatment-experienced cirrhotic patients, irrespective of GT-1 subtype.
Merck & Co will also be presenting data from the Phase II C-SALVAGE study, which is investigating the efficacy of 12 weeks of grazoprevir/elbasvir + ribavirin in patients who have previously failed treatment with interferon plus a direct-acting antiviral (DAA) therapy. The company has stated that all 79 patients who had previously failed protease inhibitor-based therapy achieved undetectable viral load at the end of treatment, suggesting that the combination maintains its potency against resistance-associated variants. While some patients may yet undergo relapse by the SVR12 time point, these data will be key for competing against Viekira Pak in treatment-experienced patients, as AbbVie did not enroll protease inhibitor-failures in its pivotal Phase III studies of Viekira Pak.
Key abstracts to watch
- The Phase 3 C-EDGE treatment-naïve (TN) study of a 12-week oral regimen of grazoprevir (GZR, MK-5172)/elbasvir (EBR, MK-8742) in patients with chronic HCV genotype (GT) 1, 4, or 6 infection.
- Efficacy and safety of grazoprevir/elbasvir +/- RBV for 12 weeks in patients with HCV G1 or G4 infection who previously failed peginterferon/RBV: C-EDGE treatment experienced trial.
- C-EDGE co-infected: Phase 3 study of grazoprevir/elbasvir in patients with HCV/HIV.
- RS-1938: C-SALVAGE: Grazoprevir (GZR; MK-5172), elbasvir (EBR; MK-
8742) and ribavirin (RBV) for chronic HCV-genotype 1 (GT1) infection after failure of direct-acting antiviral (DAA) therapy.
Potent early-phase regimens could shorten treatment duration to six or eight weeks in non-cirrhotic and cirrhotic patients, respectively
In a bid to show differentiation from first-generation oral regimens which are set to dominate the market, Gilead and Achillion will be presenting Phase II data from studies assessing their early-phase combinations in treatment durations as short as six weeks.
Achillion will be presenting updated data from the Phase II PROXY study, which has previously shown that 100% of treatment-naïve non-cirrhotic GT-1 patients (12/12) achieved SVR12 after just six weeks of treatment with Sovaldi + ACH-3102. When compared to the disappointing cure rates achieved in Merck & Co’s comparable C-SWIFT study (87% after six weeks), these data position ACH-3102 as a best-in-class NS5A inhibitor, and suggest that six-week treatment is viable for non-cirrhotic treatment-naïve patients if highly potent compounds from each class are combined. However, preclinical data suggest that Achillion’s nucleotide NS5B inhibitor, ACH-3422, possesses inferior potency to Sovaldi, and it is therefore unclear if such impressive cure rates will be maintained when ACH-3422 is substituted in for Sovaldi.
Gilead will be presenting data from a Phase II study investigating short treatment durations with sofosbuvir/GS-5816 plus the pan-genotypic protease inhibitor GS-9857. Notably, the analysis will include cirrhotic patients and will prove valuable in determining the minimum required treatment duration to achieve acceptable cure rates (≥95%) in this difficult-to-treat subgroup. This question is particularly pertinent to payers because cirrhotic patients currently require expensive treatment ranging from 12 to 24 weeks in length. Regimens capable of shortening treatment durations to less than 12 weeks could therefore provide huge savings and will possess a significant commercial advantage over currently marketed products. Based on previously released C-SWIFT data (95% SVR4 after eight weeks), Datamonitor Healthcare believes that eight-week treatment is an achievable goal for treatment-naïve cirrhotic patients, although treatment-experienced patients are likely to require a longer 12-week course.
Key abstracts to watch
- Safety and efficacy of short-duration treatment with GS-9857 combined with sofosbuvir/GS-5816 in treatment-naïve and DAA experienced genotype 1 patients with and without cirrhosis.
- Preclinical profile of the pan-genotypic HCV NS3/4A protease inhibitor GS-9857.
- Sustained virologic response after ACH-3102 and sofosbuvir treatment for 8 or 6 weeks: a Phase 2 “PROXY” study.
- Achievement of SVR12 despite the presence of HCV variants resistant to first generation NS5A inhibitors in genotype-1 hepatitis C patients after 8-week therapy of ACH-3102 in combination with sofosbuvir.
- ACH-3422, a novel nucleotide prodrug inhibitor of HCV NS5B polymerase.
Interferon/NA combination therapy is expected to provide minor boosts to cure rates in chronic hepatitis B patients
Data from four studies of Pegasys (peginterferon alfa-2a; Roche) in combination with potent nucleos(t)ide analogs (NAs) will be presented at the 2015 International Liver Congress, reflecting increased interest in the potential of combination therapy to increase hepatitis B surface antigen (HBsAg) loss and/or the sustainability of off-treatment responses (virologic suppression and normalization of alanine aminotransferase levels). Based on previous data from the ARES and OSST studies, which assessed the impact of Pegasys add-on or switching therapy in patients who had achieved virologic suppression on NAs, Datamonitor Healthcare believes that improvements in HBsAg loss or sustained off-treatment responses will be relatively minor. Nevertheless, the studies are expected to lend further credence to early-phase immunomodulatory approaches (TLR-7 agonists and a therapeutic vaccine) being developed by Roche and Gilead, which aim to stimulate sustained immune control of infection in order to increase rates of HBsAg loss. It is also important to note that rates of HBsAg loss have been shown to gradually increase over time post-Pegasys treatment, and so the true curative potential of novel immunomodulatory therapies may only be observed after several years of follow-up.
Key abstracts to watch
- A randomised prospective open-label trial comparing peginterferon + adefovir and peginterferon + tenofovir versus no treatment in HBeAg negative chronic hepatitis B patients with low viral load: analysis of week 48 results.
- Add-on peginterferon alfa-2a significantly reduces HBsAg levels in HBeAg-negative, genotype D chronic hepatitis B patients fully suppressed on nucleot(s)ide analogue treatment: the HERMES study.
- Add on peginterferon to adefovir enhances HBsAg loss in inactive HBV carriers.
- Adding tenofovir to pegylated interferon enhances end of treatment HBsAg loss in HBeAg negative chronic hepatitis B patients.
Posted in Infectious Diseases.